It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This funding opportunity announcement invites applications for the NIH-CASIS Coordinated Microphysiological Systems Program for Translational Research in Space for projects designed to leverage recent advances in tissue engineering and microfabrication to create microphysiological systems and organ-on-chip technology platforms that recapitulate human physiology under the extreme environment of space. The overall objective of the program is to better understand the molecular basis of human disease and/or the effectiveness of diagnostic markers and therapeutic intervention for disease treatment. This FOA focuses on the deployment and further development of tissue-on-chip technology to facilitate research at the International Space Station U.S. National Laboratory (ISS-NL) and to integrate results from that research into an improved understanding of human physiology. This FOA will ultimately advance biomedical research approaches and clinical technologies for use on Earth and in space, and research in Earth- and space-based facilities that could improve human health on Earth and in space. An essential feature of this FOA is a requirement for a multidisciplinary approach that brings together experts in bioengineering, microfluidics, material science, "omic" sciences, computational biology, disease biology, pathology, electrophysiology, pharmacology, biostatistics and clinical science.

Funds from the NIH will be made available through the UG3/UH3 cooperative agreement award mechanism. The initial two-year UG3 phase will support studies to develop microphysiological systems that will interrogate tissues-on-chip onboard the ISS-NL. These funds will be utilized to conduct preflight ground development and validation, NASA flight certification to support on-orbit experiment operations, and post flight data processing. The two-year UH3 phase will support studies that build upon findings from the UG3 phase. The funds will be utilized to conduct preflight ground development and validation, NASA flight certification to support on-orbit experiment operations, and post flight data processing. Center for the Advancement of Science in Space (CASIS) will provide the transportation of the experiments to the ISS-NL, support on the ISS-NL, and return of the experiments from the ISS-NL to the ground for both the UG3 and UH3 phases.

More than 30% of promising medications have failed in human clinical trials because they are determined to be toxic despite promising pre-clinical studies in 2-D cell culture and animal models, and another 60% fail due to lack of efficacy. The challenge of accurately predicting drug toxicities and efficacies is in part due to inherent species differences in drug metabolizing enzyme activities and cell-type specific sensitivities to toxicants. To address this challenge in drug development and regulatory science, the NIH in partnership with DARPA, FDA, and more recently the pharmaceutical industry has invested in the Microphysiological Systems, also known as Tissues-on-Chips (TCs) program to develop alternative approaches that would enable early indications and potentially more reliable readouts of toxicity and efficacy.

The Tissues-on-Chips program (http://www.ncats.nih.gov/research/reengineering/tissue-chip/tissue-chip.html) supports an innovative approach to preclinical toxicity testing on human tissue: development of in vitro, three-dimensional organ systems from human cells on bioengineered platforms that mimic in vivo tissue architecture and physiological conditions in order to facilitate and accurately monitor key organ-level functions. The platforms incorporate complex factors found in vivo, including extracellular scaffolding, three-dimensional structure, cellular interactions (including between different cell types), perfusion, biomechanical stresses (e.g., stretch and shear forces from fluid flow), electrical stimulation of excitable tissue, hormone responses, etc. Tissues-on-Chips are useful tools for predictive toxicology and efficacy assessments of candidate therapeutics. The initial MPS program is a five-year partnership between NIH, DARPA and FDA. Prior NIH investments through (RFA-RM-11-022) and (RFA-RM-12-001) supported the development and integration of bioengineered multi-organ systems, along with the generation of renewable human cell resources for predictive assessment of drug safety and toxicity.

The ISS-NL provides an extraordinary research platform for experiments in the biological and medical sciences. Microgravity induces a vast array of changes in organisms ranging from bacteria to humans, including global alterations in gene expression and 3-dimensional aggregation of cells into tissue-like architecture. Moreover, studies of astronauts reveal a variety of space flight-induced health conditions, many of which may serve as models of ground-based ailments such as aging and trauma. Research into these and other effects of the space environment may advance pharmaceutical development and augment Earth-based studies in basic and human biology.

The NIH and the Center for the Advancement of Science in Space (CASIS) have partnered and executed a memorandum of understanding (MOU) to collaborate and coordinate efforts that will help refine tissue chip technology for biomedical research use at the ISS-NL. The ability to conduct biomedical research in space using tissue chip technology provides unprecedented opportunities to study the effects of microgravity, reduced-gravity environments at the ISS-NL and radiation exposure and its effects on many of the human body's systems. It is now widely known that accelerated aging takes place in space due to muscle wasting, osteoporosis, reduced cardiopulmonary function, altered immune response, etc, but that these conditions are reversible when astronauts return to Earth. It is anticipated that this FOA by NIH and CASIS will delve into the molecular basis, including epigenome changes, for these human conditions and provide information for novel targets for drug development and innovative treatment modalities. Translation of this research to the ISS-NL promises to accelerate the discovery of molecular mechanisms that underlie a range of common human disorders and advance understanding of therapeutic targets and treatments in a reduced fluid shear, microgravity environment that recapitulates cellular and tissue matrices of Earth.

The following constitute distinct and unique advantages for conducting biomedical research in space:

• Effects of microgravity:
• Altered gene expression results in phenotypic consequence, including changes in cellular immune function and microbial growth and virulence
• Cell cultures show altered processes of differentiation and cell communication, including increased pluripotency of stem cells
• Tissue cultures grow in three dimensions
• Changes in body systems result in bone loss, immunosuppression, vision changes, viral reactivation and loss of skeletal muscle mass and strength, among other effects
• Some studies show growth of larger and more highly ordered crystals of proteins and large molecules (versus ground studies)
• Radiation environment:
• Includes high energy protons and atomic nuclei of heavier elements

An informational webinar hosted by NCATS and CASIS NOT-TR-16-011 was held April 28, 2016. Materials, FAQ, and contact information of CASIS implementation partners can be found at http://casistissuechip.blogspot.com/. An additional informational webinar was held September 6, 2016 and further details can be found at http://casistissuechip.blogspot.com/.

CASIS:

CASIS manages the International Space Station ( ISS ) National Laboratory ( NL ) in accordance with NASA Cooperative Agreement No. NNH11CD70A, CFDA 0043-007. Among CASIS goals are efforts to fully utilize the ISS-NL and enable technology that enhances utilization of the ISS-NL by commercial interests, other government agencies, and educational entities.

CASIS intends to allocate in-kind resources of an estimated value of $8M that will be utilized to enable the NIH-awarded spaceflight investigations. These in-kind resources will include, but are not limited to, a portion of the total scope spaceflight mission management, all of the required transportation to and from the International Space Station, all of the required on-orbit crew time, as well as other resources and coordination activities as are necessary to conduct the awarded microgravity investigations. CASIS will also provide the following to NCATS Awardees:

• Coordinate with awardees to obtain final approval and manifest for flight by NASA
• Coordinate with NASA and awardee’s selected Implementation Partner for on-orbit access to appropriate testing facilities. It is anticipated that CASIS and its Implementation Partner will support awardees in arranging for the required flight to the ISS-NL.
• Assist awardees by coordinating with third parties, including NASA and Implementation Partner, in order that User may obtain appropriate resources to allow User to effectively conduct research and development on the ISS-NL.
• Assist awardees to identify and coordinate ground-based pre-flight and post flight resources at launch and primary landing or alternate landing sites.
• CASIS and NIH will prioritize awardee’s research prior to sending to NASA for its integrated prioritization and approval. If approved, CASIS will coordinate on-orbit space flight on the ISS-NL.

Template agreements have been developed for this program to streamline the processes of forging partnerships between CASIS and awardees, and include Confidential Disclosure Agreements (CDAs) and Collaborative Research Agreements (CRAs), which will provide the framework for partnerships.

Implementation Partners:

Implementation Partners are experienced payload developers and subject matter experts who can provide a wide range of products and services to aid in the payload integration process, and have demonstrated experience to ensure scientific success. Implementation Partners provide unique suites of flight certified hardware, and services include:

• Technical guidance to translate ground-based science goals to the space environment
• Engineering integration
• Hardware/software development and testing
• Flight qualification services
• Mission management
• Launch
• Landing site support
• Operations planning and real-time crew operations support

The Tissue-on-Chips Consortium (The TC Consortium)

The NIH TC for Drug Screening Program is led and managed by NCATS and utilizes expertise (organ physiology, regulatory science, stem cells, bioengineering, etc.) from experts from other Institutes, Centers and Offices at the NIH and CASIS. Additional expertise from FDA and industry, such as through NIH partnership with the IQ Consortium allows for pharmaceutical companies to work with NCATS staff and TC Consortium investigators on context of use, marketability and potential stakeholder feedback-elements crucial to move past the discovery/innovation phase. The TC Consortium, which comprises all these partnerships, plus several new industry collaborators, holds an in-person meeting every 6 months and plays a pivotal role in advancing the MPS technology. Awardees from this FOA will become members of the TC Consortium and be expected to attend biennial meetings.

Among the areas of research encouraged in this proposed initiative are translational research examining the mechanisms that underlie the effects of diseases or conditions associated with bone and cartilage, skeletal muscle, brain, gastrointestinal tract, lung, liver, microvasculature, skin, or other tissues, as well as research designed to improve the translation of existing knowledge of strategies for the prevention and treatment of such diseases or conditions.

It is possible, through research at the ISS-NL, to exploit space-specific phenomena to conduct inflight studies using tissue chips that include:

• Altered gene expression to study biological processes, such as virulence, or protein and antibiotic production
• How cell cultures respond to space-related stressors and various altered processes
• Use 3-D tissue cultures to repeat ground-based studies of pharmaceutical effectiveness, necrosis and tissue growth techniques
• Study microgravity-induced health conditions to inform the treatment of ailments such as osteoporosis, immunosuppression and shingles, as well as the prevention of age-induced physiological changes
• Novel pharmaceutical design/targets based on a better understanding of pathogenesis, as well as improved production methods and higher sensitivity and specificity of drugs
• Development of viral vaccines and new drug treatments using tissue chips
• Elucidation of biological pathways and characteristics of cell interactions
• Increased translational relevance of studies on cell/tissue behavior and response to stimuli (such as pharmaceutical testing)
• Advanced tissue engineering and regeneration using tissue chip technologies
• Design of approaches to improve wound healing
• Advancements in therapeutic approaches to diseases on Earth and anti-aging biology
• Post flight recovery of tissue chips for genomic, proteomic, metabolomic, epigenomic and histological analysis
• Capability to integrate remote monitoring and control of on-orbit tissue chips from the ground

Each UG3/UH3 application should be structured to meet the NIH-CASIS program goals. It is anticipated that the UG3 phase will involve studies on ground development of tissue chip technology under microgravity environments which includes working with CASIS ISS Implementation Partners, testing and pilot experiments under simulated environments, flight integration, conduct of experiments at the ISS-NL, and post flight analyses. Successful UG3 projects will transition into the UH3 phase for re-flight and more extensive experiments and analyses.

The models are expected to express critical aspects of human physiology and provide a measurable output for the representative systems. In developing tissue chip models that more accurately represent human physiology and pathology, primary tissues obtained from patients may be used; however, investigators are strongly encouraged to take advantage of recent advances with human stem cells, progenitor cells, induced pluripotent stem cells (iPSC), and gene editing technologies to engineer tissues whenever feasible. Essential characteristics of the models should include all or some of the following features: 1) multicellular architecture that represents characteristics of the tissues or organs of pathology; 2) functional representation of normal and diseased human biology; 3) reproducible and viable operation under physiological conditions maintained up to 4 weeks in culture; 4) accurate representation of normal and disease phenotypes; and 5) representation of diversity or heterogeneity of human population. Ideally the platform used should be compatible for operation at the ISS-NL using ground-based controls, or transmit to ground control assay outputs that include multiple molecular read-outs, such as gene expression, proteomic, metabolomic, or epigenomic analyses. The bioengineered platform should also provide spatial and temporal control of the cellular microenvironment, while enabling continuous monitoring (sensing), probing (direct in-cell measurements), and sampling (testing and continuous data collection and analysis) of the system.

A flight experiment should be proposed for each of the UG3 and UH3 phases. Selected projects must be flight ready within 16-18 months of the specific award period. If flight schedules change, investigators may modify proposed timelines, subject to review and approval by the NIH Program Officer in coordination with CASIS.

Major Goals of the UG3 phase:

1. Develop in vitro models using primary tissue or iPSC-derived patient cell sources on tissues/organ-on-chips platforms. Models should demonstrate a functional representation of normal and diseased human states

2. Determine the relevance of models by preliminary testing of key experimental features and outcomes during the initial flight to the ISS-NL. Successful outcome will determine which UG3 projects will proceed to the UH3 phase of the study. This would include, for example, inclusion of non-invasive endpoints that generate reproducible data under physiological conditions over a prolonged culture conditions at the ISS-NL; platform integration to study multiple organ pathology; and representation of population diversity. The functional validation of the tissue chips may be model-specific.

Major Goals of the UH3 phase:

The major goals are to demonstrate the functional utility of the models for understanding the effects of microgravity on human physiology, the potential to identify novel targets for drug screening, the assessment of candidate therapies for efficacy and safety assessments, and the establishment of pre-clinical foundations that will inform clinical trial design. To achieve this, the applications will focus on outcomes that may include:

• Cross-validation of model end-points with clinical measures in humans
• Characterization of the parameters of response to exposure to the space environment on the ISS
• Developing translatable, pharmacodynamics (i.e., target engagement) biomarkers for well validated therapeutic targets
• Conducting preclinical efficacy testing of candidate therapeutics using innovative approaches, data acquisition and analyses
• Extensive characterization and clinico-pathological staging in the models with the corresponding stages of clinical disease using translatable biomarkers
• Developing strategies for rapid, open-access dissemination of data, and methodology and, for rapid distribution of models for their use in therapy development

Transition from the UG3 to the UH3 Award

Transition to the UH3 award will depend on the successful achievement of general and model-specific benchmarks, the feasibility of study continuation, a proven ability to work within a consortium arrangement with other awardees and CASIS Implementation Partners, and the availability of funds. The UH3 awards will be made after administrative review of progress in the UG3 phase to investigators whose UG3 projects have successfully met their milestones, demonstrated functionality and validity of their model systems, and have well-conceived plans to fully utilize the models for more extensive testing on the ISS-NL during the UH3 phase. There will be an Administrative Review Panel derived from the Tissue Chips Project team composed of NIH extramural program from the participating NIH Institutes to monitor the progress and achievement towards milestones. UG3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 stage. CASIS will provide input to NIH Extramural Program Staff on the feasibility of the projects for the next phase.

Awardees will submit a progress report to both the Grants Management Specialist and the NIH Program Official upon completion of the UG3 milestones and any revisions to the proposed UH3 aims. Prior to initiation of the UH3 stage, an updated human subjects protection plan (e.g., protocol amendment, IRB approval of amendments to the protocol or consent form, etc.) and a detailed data and safety monitoring plan (DSMP) if appropriate, must be approved by NIH.

Milestones and Timeline:

A timeline (Gantt chart) including milestones is required for all studies. Milestones are benchmarks that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. UG3UG3Selected projects must be flight ready within 16-18 months of the specific award period.

Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UG3 and UH3 milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and applicant will negotiate and agree upon a final set of approved UG3 milestones which will be specified in the Notice of Award.

Studies of Particular Interest

Applicants should seek to use microphysiological systems in microgravity to interrogate tissues-on-chips for bone and cartilage, skeletal muscle, brain, gastrointestinal tract, lung, liver, microvasculature, skin, or other tissues. Areas of particular interest are identified below, but are not limited to:

• Development of models of human organ system from human embryonic or induced pluripotent stem (iPS) or progenitor cell lines. The microsystems should model aspects of the 3-dimensional architecture and cellular composition of the target organ, such that a specific normal or pathological function of interest for addressing a specific biological question can be recapitulated in microgravity.
• Development of assays for toxicity or efficacy assessment that reflect relevant functional readouts of the organ system in microgravity (e.g., contractile response to chronotropic drugs).
• Development of cell-type specific reporter or biosensor systems that will enable assessment of the cellular architecture and functional output of the microsystem to capture the dynamics of biological responses in microgravity.

UG3 Phase

During the UG3 phase, the NIH is interested in supporting the development and initial validation of tissue chips to model human diseases and conditions acquired during prolonged exposure to microgravity where the primary site of pathology affects the following organ systems: circulatory, endocrine, gastrointestinal, immune, integumentary, musculoskeletal, nervous, sensory, reproductive, respiratory and urinary. It is anticipated that model systems, where appropriate, will address multi-organ or multi-systems affectations of the pathology being modeled, such as physiological effects of disturbances in circadian rhythm. Examples of microsystems and potential disease modeling for the organ systems after prolonged exposure to microgravity are listed below and may include, but are not limited to:

Circulatory:

• Changes in the circulatory and lymphatic systems, including cardiovascular and cerebrovascular changes, stiffening of the arteries, hypertension, upper body fluid shifts, bone-vascular interactions as determinants of bone growth

Nervous:

• Changes in the nervous system, including disturbances in sensorimotor integration, changes to the autonomic nervous system leading to orthostatic intolerance and sleep disorders
• Neurologic, neurodegenerative, neurodevelopmental changes leading to ataxia, postural disturbances, perceptual-motor functioning, neuromuscular weakness, and fatigue, learning and memory and basic cognitive deficits

Sensory:

• Changes in the sensory systems that affect the eye, ear, olfaction, gustatory, tactile senses
• Physiological representative chip models that recapitulate a functioning vestibular system, with special relevance to space adaptation syndrome (SAS)
• Targeted vestibular membrane proteins, such as K channels and various subtypes, to better assess pharmacological agents and lead to alleviation of vestibular dysfunction
• Chip models that might lead to better understanding of changes and alterations of vestibular and auditory afferent fibers during vestibular sensorimotor dysfunction
• Vestibular developmental studies to understand cell type changes and functions in microgravity
• Constructing a basic haircell-neural system on a chip to test how lack of normal gravity affects synaptic release and reception of neurotransmitter molecules; could be for efferent as well as afferent systems.
• Distorted vision
• Loss of taste and/or smell

Adipose:

• Pathophysiology of fat tissues that occurs in disease states such as diabetes, obesity cancer, HIV and lipodystrophies. Human fat depots of interest include:
• White adipose tissue, including visceral fat [that is associated with insulin resistance, low grade inflammation, dyslipidemia, and cardiometabolic risk, and subcutaneous white fat that has beneficial characteristics including storage of lipid, secretion of adipokines, positive metabolic effects such as lipid oxidation, energy utilization, enhanced insulin action, and an anti-inflammatory role
• Brown adipose tissue, specialized to burn fuels and perform thermogenesis, including, classical brown adipocytes and brown adipocyte-like cells, also called beige/brite cells, which arise in white adipose tissue in response to cold and hormonal stimuli
• Marrow adipose tissue (MAT), which is functionally distinct from both white and brown adipose tissue, and can contribute to systemic and skeletal metabolism. Systems looking at cross talk of fat chips with tissues chips of skeletal muscle, liver, pancreas, skin, and bone are of particular interest.

Endocrine:

• Changes involving dysregulated hormone release or endocrinopathies, including activation of sympathetic-adrenomedullary system and hypothalamic-pituitary-adrenocortical axis, inhibition of hypothalamic-pituitary-gonadal/glandular function

Gastrointestinal:

• Gastrointestinal disturbances such as inflammatory bowel disease and other inflammatory conditions, gut dysmotility, functional gastrointestinal disorders, gut injury and healing, and enteric infections
• Diseases of the exocrine pancreas, such as acute and chronic pancreatitis, and pancreatic neuroendocrine tumors; inter-relations between the exocrine and endocrine components in both physiology and pathobiology of the pancreas
• Liver fibrosis, steatosis, cholestasis, and immunological and toxic cell injury, and liver diseases such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cholestatic liver diseases, autoimmune liver diseases, viral hepatitis, metabolic liver diseases, and genetic liver diseases
• Where relevant, systems modeling gastrointestinal and liver diseases should include interaction with the microbiota and/or investigation of multi-tissue interactions in combination with other organ tissue chips

Immune:

• Microsystems that can model immune system dysregulation and disease pathologies such as inflammation, complement activation, dendritic cell activation, autoimmunity, allergy, hypersensitivity, infectious disease

Musculoskeletal and Skin:

• Diseases affecting bone, disc, joint, muscle, skin and skin appendages, tendon and ligaments; including atopic dermatitis, psoriasis, muscular dystrophies, muscle inflammatory and/or wasting diseases, osteoporosis, osteoarthritis, rheumatoid arthritis, and other rheumatic diseases

Dental, Oral and Craniofacial:

• Modeling mechanistic aspects of oral mucositis and screening promising therapeutic approaches to alleviate mucositis using oral mucosa and tongue TCs
• Establishment and validation of salivary gland TC, and investigation of mechanisms of salivary gland dysfunction, xerostomia, transformation and cancer, and identification of approaches to prevent and treat these conditions
• Establishment and validation of periodontium TC containing multiple tissues comprising human periodontium, modelling progression of periodontal disease and investigation of interactions between periodontium and oral microbiome
• Elucidation of mechanisms of craniofacial bone development and craniofacial disease utilizing craniofacial bone and bone-suture TCs
• Identification and functional screening of promising therapeutic compounds that can augment and enhance DOC tissue regeneration

Endocrine Pancreas and Pancreatic Islet:

• Models that closely mimic the physiology and tissue crosstalk between the pancreatic islet and other organs to generate human disease models of diabetes (T1D, T2D, and MODYS). These systems should integrate physiologically accurate human models of the islet and other tissues, including the liver, exocrine pancreas, gut, fat depots, skeletal muscle, and the addition of innate and adaptive immune/inflammatory components
• An integrated platform that supports a bimodal islet and liver microsystem that could monitor in real-time, quantitatively and at high resolution, some of the following in a normal and diseased state:
• islet health and function, including glucose-sensitive insulin release and glucagon secretion for up to 4 weeks, delivery of secreted products from islet to liver using microfluidics technology
• liver responsiveness to insulin, incretins, adrenergic stimulation, glucagon and other secreted factors
• effects of glycemic excursions, and nutrients on liver metabolism, glucose output, cholesterol, triglyceride synthesis, protein synthesis, energy metabolism and biliary excretions, quantitative measure of lipids, metabolites and proteins in the chip using single cell imaging technology
• introduction of GI hormones, nutrients and other substances to the liver chip using microfluidics technology to mimic a portal system

Reproductive:

• Disease models affecting the female reproductive system and women’s health (e.g., endometriosis, fibroids, preterm birth, sexually transmitted diseases, etc.)
• Establishment and validation of a female reproductive system which closely mimics the normal physiology of a woman during pregnancy and crosstalk between organs (e.g., liver, heart, kidneys)
• Establishment and validation of male and female reproductive system TC models which test efficacy and toxicity of candidate drugs used for treatment of cancer (e.g., cervical cancer)
• Functional integration of the male or female reproductive system with other tissue/organ TCs
• Study of sex differences in disease onset, progression, and response to therapy

Respiratory:

• Disease models of pulmonary hypertension, cystic fibrosis, bronchiospasm, asthma
• Disease models that would enable evaluation of exposures to respiratory pathogens, smoke inhalation or inhalation of toxic substances

Kidney, Urinary and Hematological:

• Diseases of the kidney or its functional unit, the nephron, including the glomerulus, functionally-distinct segments of the tubule, interstitium, and other relevant cellular compartments, and their interactions
• Stress on kidney function due to shifts in fluid dynamics in microgravity, including investigating glomerular atrophy, interstitial edema and degeneration of renal tubular cells
• Diseases of the lower urinary tract that manifest as complications of diabetes
• Diseases of the lower urinary tract, including the urinary bladder for both men and women; modeling of physiology or pathology of the lower urinary tract, which may include the role of the urinary microbiome and/or urologic chronic pelvic pain syndromes for both men and women
• Diseases of the prostate
• Development and validation of TCs that closely mimic the normal physiology of the hematopoietic stem cell niche; that then allow for elucidation of factors responsible for maintenance of hematopoietic stem cells or fate decisions, with a focus on the myeloid lineage, using TCs; and elucidation of factors responsible for homing and engraftment of hematopoietic stem cells in settings of bone marrow failure or irradiation
• Functional integration of kidney, genitourinary, or hematopoietic niche TCs with other relevant tissue/organ TCs

Other:

NIH is also interested in systems that have the unique ability to monitor and evaluate changes due to extreme radiation exposure to syngeneic models inflight and on the ground, systems that can provide measures of anti-tumor activity and target organ toxicities simultaneously, as well as systems that may enable the study of biological markers of response to anticancer treatments (e.g. shedding DNA or cells, microvesicles, etc.).

In addition, NIH is interested in models that interrogate the role of the space environment, including the effects of microgravity and/or radiation, in health and disease to elucidate disease mechanisms and identify novel biological pathways as the basis for developing safe, effective treatments, as well as prevention planning and public health strategies. Tissue Chips promise to be valuable tools in elucidating the role of exposure or in concert with factors that might enhance or mitigate exposure outcome. Specific areas of interest include, but are not limited to:

• Production and characterization of TC panels using either primary cells or iPSC-derived cells - representative of community, ethnic, or regional demographics to provide insights into individual and population susceptibility to exposures
• Accounting for heterogeneity of response due to human population diversity in concert with environmental or endogenous stressors
• Demonstrations utilizing TC of improvement over current assays on human tissue for early biomarkers of disease; including genome integrity, DNA damage and repair, receptor activation, metabolism and metabolic competence, and toxico-kinetics
• Establishment of TC for discovery and validation of biomarkers of environmental exposure. These include development of models of environmentally influenced diseases that replicate pathological and physiological end points. Studies of signaling among cells and tissues that could provide new insights into environmental diseases are also encouraged.
• Production of TC based on iPSC of cells/tissues of brain or solid organs, such as heart and lungs, from which human tissue is not readily accessible in order to facilitate new insights into the roles of exposure.
• Integration of tissues relevant to multiple organ systems to understand how tissue interactions influence disease pathogenesis, comorbidities, and treatment.

Desired model characteristics may include, but are not limited to the following:

• Innovative and creative approaches using tissue-on-chips technology towards 3-D models that include relevant anatomical and cellular elements
• Integration of specific TC models with other organ systems to understand how tissue interactions influence disease pathogenesis, comorbidities, and treatment
• Inclusion of immune elements (e.g., macrophages, neutrophils, or mucosa-associated lymphoid tissue)
• Inclusion of site-specific microbiota, where appropriate
• Accurate reflection of human host - pathogen interactions, where appropriate
• Capacity to test biomarkers or candidate therapeutics
• Development of markers or readouts to confirm that the model(s) of interest mimic human pathology and conditions
• Applying genome manipulation strategies, such as CRISPR/Cas9, Talen and Zinc-finger to introduce relevant variants where appropriate

Additional Considerations

• Cells: The use of transformed or immortalized cell lines is discouraged, except for preliminary, proof of concept studies. The use of primary cells, organ explants, or pluripotent stem cells, e.g., iPSC, is encouraged. Multipotent or unipotent stem cells also may be utilized where appropriate. The current NIH guidance on stem cell usage can be found at http://stemcells.nih.gov/policy/pages/2009guidelines.aspx .
• Biomaterials: Native extracellular matrices (ECM) are dynamic, complex microenvironments that can drive functional and biomechanical development. Applicants should consider the biological properties and potential downstream effects when choosing ECM materials.
• Biomaterials should be chosen to avoid confounding characteristics, e.g., the plastic polydimethylsiloxane (PDMS) binds hydrophobic drugs or reagents, which decreases the intended concentration, and can leach the endocrine disruptor cyclosilane into the medium.
• Collaborative Interactions are a critical piece of this FOA. Model system(s) development will require extensive collaboration between tissue engineering/tissue biology experts and the disease experts and clinicians, as well as engagement of CASIS Implementation Partners.

Technical Feasibility

In order to utilize the ISS-NL, NASA has specified details regarding payload integration requirements, available at https://casis.box.com/v/PayloadIntegrationProcess.

CASIS strongly recommends Investigators work with Implementation Partners that have experience developing NASA flight certified payloads. Lists of Implementation Partners can be found at http://casistissuechip.blogspot.com/ as well as http://www.iss-casis.org/CASISBasics/ForResearchers/DirectoryofImplementationPartners.aspx. Please contact CASIS, chipsinspace@iss-casis.org, with any questions or concerns.

Investigators are strongly encouraged to contact a CASIS representative, at chipsinspace@iss-casis.org, as early as possible in order to receive guidance on the technical feasibility component of their applications prior to submission to the NIH. This interaction with CASIS is crucial for providing guidance on which CASIS Implementation Partner would be most appropriate for partnering with the applicant. Implementation Partners are experienced payload developers and subject matter experts who can provide a wide range of products and services to aid in the payload integration process, and have demonstrated experience to ensure scientific success.

Awardees may be required to travel to support critical project activities related to experiment design/development, payload development, experiment and payload verification testing, design reviews, ISS crew training, and/or other required ISS payload integration process requirements.

Applications that do not include the following information will not be reviewed:

• Applications that do not include a complete description of how the technical feasibility requirements will be met.
• Applications that do not address the NASA payload integration requirements.
• Applications that do not propose the use of the ISS-NL as part of their UG3 and UH3 applications, for example, or the use of simulated microgravity as the end goal of the application.)

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Mohan Viswanathan, Ph.D.
Telephone: 301-312-3745
Fax: 301-480-3660
Email: mv10f@.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

PDs/PIs are required to attend an initial kick-off meeting and bi-annual Consortium Meetings in the Washington, D.C. area. Funds to support travel of the PD(s)/PI(s) to attend the kick-off and bi-annual Consortium Meetings should be included in the budget

Applicants should also request funds for travel expenses related to critical project activities related to experiment design/development, payload development, experiment and payload verification testing, design reviews, ISS crew training, and/or other required ISS payload integration process requirements after interaction with Implementation Partners to define the anticipated frequency, location, and approximate budget of travel.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Provide the overall goals or hypotheses for the entire project period and indicate separate Specific Aims to be accomplished in the UG3 phase and in the UH3 phase.

Research Strategy: Applicants should provide a rationale for the choice of human pathology to be modeled in space, and the bioengineered platform to be used. Applicants should include a description of the proposed interactions with CASIS Implementation Partners or alternative methods to satisfy NASA payload integration requirements, as well as, the approaches to characterize the models and identify novel biology/mechanisms that could aid in novel targets for treatment.

• Provide separate sections that describe both the UG3 and UH3 phases
• Provide a description of the hypothesis to be tested in the UG3 phase of the study
• Include a discussion of past experience and successes with the preclinical studies proposed and experience developing required documentation for the conduct of related clinical studies
• A description of how the trial will be organized and managed, including the plans to identify and select additional collaborators, if applicable
• A description of the consortium arrangement with other awardees and CASIS implementers to meet the program goals

Milestones

The application must include clearly-specified, well-defined milestones, quantitative go/no go decision points, and timelines for assessing progress in both the UG3 and UH3 stages, including specific milestones and timeline for progressing from the UG3 stage to the UH3 stage.

Milestones and the timeline for each stage must be provided in a separate heading at the end of the Approach section for each UG3 and UH3 component and include the following:

• detailed quantitative criteria by which milestone achievement will be assessed;
• detailed timeline for the anticipated attainment of each milestone and the overall goal; and
• any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Go/No-Go Transition Milestone for transition from the UG3 Phase to the UH3 Phase

• Include a clearly identified Go/No-Go transition milestone for completion of the UG3 phase at the end of Year 2 and transition to the UH3 phase for 2 years of additional funding.

A description of the UH3 phase protocol specific milestones should be included at the end of the UH3 section. Also include a discussion on potential delays, and alternates for conducting the study in the face of adverse outcomes or problems in sufficient detail to inform the likelihood of accomplishing the trial in the time proposed.

Technical Feasibility

Applications must clearly describe how the NASA payload integration requirements will be met. Specifically, the technical feasibility details should include logistics, hardware, projected time frame, hazards, and research questions. Applications may be considered technically unfeasible for flight research if a detailed description of proposed flight hardware is not included, and the NASA payload integration requirements are not addressed. Such applications deemed unfeasible will not be funded.

Specifically, the technical feasibility details should include the following elements:

• Logistics: Proposed resources including Implementation Partner support, facility needs for ground testing and flight operations support, use of ISS crew for research support, power and data requirements, weight, and any known hazards
• Hardware: Availability, limitations, appropriate planned use and (alternatively) the costs and feasibility of proposed new hardware development
• Projected Time Frame: Preflight development and testing considerations, time to flight and time to completion
• Hazards: Procedures, situations and materials that could potentially be hazardous and a plan to mitigate any identified issues
• Research Questions: How results will be collected, analyzed, and interpreted. Identifications of potential barriers and ideas for alternative approaches.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

All instructions in the SF424 (R&R) Application Guide must be followed.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Specific to this FOA: Is strong justification/rationale provided for potential translational benefit derived from the use of the proposed models? Has the applicant included an adequate description of the disease, condition, intervention or environmental exposure? How will the created disease models be able to recapitulate specific alleles and genomic, proteomic, metabolomic and other biological indicators of the disease(s) of interest? Does the application focus on critical gaps to address important questions or obstacles in the particular diseases of interests? Will successful completion of the research aims improve the understanding of disease pathogenesis and advance the development of diagnostics and interventions?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?Specific to this FOA: Does the application provide a feasible strategy for collaboration among the scientific fields relevant to this FOA, i.e. disease experts, clinicians, patient groups, tissue chip developers, implementation partners? Is the Multi-PI leadership plan well-described, including plans for dispute resolution? Have project leadership and other key personnel demonstrated a record of directing research activities related to creating and validating models of disease?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Specific to this FOA: Does the project utilize the current advances of genome editing and other cutting-edge technologies? Are the tissue chip platform and cells being proposed suitable to capture the features for the disease?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? Specific to this FOA: Are the proposed approaches, tools and technologies state-of-the-art and scientifically justified for the particular model? Are the conceptual frameworks, testable hypotheses, design, methods and analyses adequately developed, well integrated, well-reasoned and appropriate to the disease to be modeled? Is the choice of the bioengineered platform, microfluidics, biomechanics and cell sources for the model system well-justified? Are the overall strategies, methodologies and analyses for conducting a translatable biomarker study well-reasoned and appropriate? Are the overall goals of the application conducive to generating significant multidisciplinary investigations that respond to the overall objectives of the FOA, i.e., generating novel models for studies of human pathology triggered by exposure to microgravity that will advance basic and translational science and/or therapy development?

Milestones and Technical Feasibility. Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risks clearly defined and feasible? Are appropriate, quantitative milestones provided for the UG3 and UH3 phases clearly defined? Are the UG3 and UH3 milestones feasible, well developed and quantifiable with regard to the specific aims of each phase? Is the timeline feasible for the UG3 and UH3 phases? Are the critical decision points (i.e. go/no go decision points) and timelines appropriate for the UG3 and UH3 phases? Are adequate criteria provided in the UG3 phase to assess milestone completion in order to make a decision to advance studies to the UH3 phase? Has the technical feasibility requirement been adequately addressed?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Specific to this FOA: Does the project sufficiently justify the necessity to utilize the unique environment present on the ISS-NL? Are the collaborations well-documented, including provision of letters of support?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not applicable

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCATS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NCATS Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Degree of ISS-NL-related technical feasibility

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

In addition, a Collaborative Research Agreement with CASIS must be fully executed prior to issue of any award. A generic copy of such an agreement can be found here.

The PD(s)/PI(s) will have the primary responsibility for:

• Defining the details and goals of the project as a whole within the guidelines of this FOA.
• Managing all data acquired in a coherent database that will be available to government and private partners.
• Coordinating, cooperating, and participating with NIH staff in the scientific, technical, and administrative management.
• When needed, working with private partners to acquire and maintain reference compounds that industry partners will provide.
• Working with NIH Program Officials and industry partners to establish context of use, standardizing and validating approaches.
• Performing established standardization and validation milestones.
• Ensuring that all affiliated staff will maintain the confidentiality of the information developed by the investigations, including, without limitation, informatics tools, protocols, data analysis, conclusions, etc. per policies approved by the consortium as well as any confidential information received by third party collaborators.
• Analyzing, publishing and/or publicly releasing and disseminating results, data and other products of the study in a timely manner, concordant with the approved plan for making quality-assured data and materials available to the scientific community and the NIH, consistent with NIH policies and goals of the FOA.
• Participating in a cooperative and interactive manner with NIH staff, TC investigators and one another.
• Sharing data, materials, informatics tools, methods, information and unique resources that are generated by the project as appropriate and in accordance with NIH policies in order to facilitate progress and consistent with achieving the goals of the MPS program.
• Participating in one in-person "kickoff meeting" held at the beginning of the award period as an organizing workshop together with NIH and CASIS staff, including representatives from the institutes supporting the awards. This organizing workshop will go over Terms and Conditions of Award for the UG3/UH3, TC Consortium responsibilities and duties, and provide an opportunity for awardees to describe their project to the consortium.
• Attending consortium meetings, which thereafter will be held in the Washington, DC area semi-annually and should be factored in the budget proposal.
• Working with the members of TC Consortium to establish agreements that address the following issues: (1) procedures for data sharing among consortium members and data sharing with industry partners, as appropriate; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing biospecimens under an overarching MTA amongst consortium members that operationalizes material transfer in an efficient and expeditious manner as appropriate and consistent with achieving the goals of the program; (5) procedures for reviewing publications, determining authorship, and industry access to publications.
• Ensuring that for activities that involve academic and/or industry collaborations within and outside the TC Consortium there are appropriate research collaboration agreements (e.g. CRA, CDA, MTA etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement terms of award as well as any additional applicable NIH policies and procedures.
• Ensuring that the research is conducted in accordance with processes and goals as delineated in this Funding Opportunity Announcement.
• Submitting a progress report to both the Grants Management Specialist and the NIH Program Official upon completion of the UG3 milestones and any revisions to the proposed UH3 aims.
• Prior to initiation of the UH3 stage, providing an updated human subjects protection plan (e.g., protocol amendment, IRB approval of amendments to the protocol or consent form, etc.) and a detailed data and safety monitoring plan (DSMP) if appropriate, for approval by NIH.
• Upon completion or termination of the project, ensuring all study materials, tools, databases and procedures developed from the project are broadly available (e.g., putting into the public domain) or made accessible to the research community according to the NIH-approved plan submitted for each project, for making data and materials available to the scientific community and the NIH for the conduct of research. The data sharing plan should include a plan to accomplish this within 90 days of the end of the study.
• Participating in regular (monthly) conference calls with all NIH and CASIS TC Project Team members
• Coordinate efforts with other awardees, especially in circumstances where synergy of efforts and resources is beneficial to the overall goals of the MPS program
• Participating in and present findings at the semi-annual workshops convened by the NIH
• Coordinate or jointly publish findings in a timely manner, and as to have the broadest impact.
• Ensure all subjects are properly consented to allow appropriate sample and data distribution to researchers in academics and industry

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

The NCATS will designate program staff, including a Program Officer to provide stewardship and administrative oversight of the cooperative agreement. The Program Officer will be named in the Notice of Award (NoA).

An NIH Project Coordinator will be substantially involved in this project as follows:

• Facilitate interactions among awardees and CASIS participants.
• Coordinate and facilitate the activities of the program, attend and participate in all meetings of the MPS consortium, and act as a liaison between the Awardee and the Cures Acceleration Network Review Board (CAN RB).
• Engage the CAN RB to provide feedback to the NCATS on Tissue Chips in Space activities. The CAN RB may review the progress of the MPS program and may advise NIH staff of opportunities that may enhance the operation and achievements of the MPS program
• Work with Science Officer(s) from the trans-NIH TC Project Team, to review the scientific progress and administrative accomplishments of the awardees, and review the project for compliance with operating policies and procedures, including meeting milestones. Based on this review, the Program Officer may recommend to the NIH to continue funding, or to withhold or restrict support for lack of progress or failure to adhere to NIH policies. Review of progress may include regular communications between the Principal Investigator and NIH staff, periodic site visits for discussions with research teams, fiscal review, and other relevant matters. The NIH retains the option of organizing periodic external reviews of progress.
• Maintain public-private partnerships established under the NCATS Tissue Chip program
• Work directly with industry and regulatory partners on maintaining or modifying standardized protocols to test MPS devices
• Provide input into the design of research activities and play a key role in coordinating research efforts.
• Monitor milestone progress and help identify recourses if needed
• Ensure that the awarded project(s) adhere to cooperative agreement data-sharing and other resource-sharing policies.
• Facilitate collaborations with and access to other NIH-supported research resources and services.
• Facilitate negotiations with companies interested in working with the awardees
• Provide advice on project management and technical performance.
• Coordinate and manage MPS Steering Committee efforts
• Provide guidance to the awardees on private-public partnerships and regulatory agency policies
• Invite experts with relevant scientific expertise to provide feedback on MPS program activities.
• The NIH reserves the right to curtail or phase out the award in the event of (1) a substantial shortfall in accomplishing the management goals and responsibilities as stated in the reviewed application, (2) failure to meet procedures and milestones, and/or (3) substantive changes in the management of award(s) that are not in keeping with the objectives of the FOA.
• The NIH will enlist additional scientific consultants as necessary from within the NIH, other government agencies, and from industry partners whose function will be to assist the Program Director in carrying out the goals and aims of the approved studies.
• Areas of Joint Responsibility include:
• Provide copies of all milestone documents to CASIS as part of the MOU between NIH and CASIS.

Areas of Joint Responsibility include:

• Collectively awardee(s) and NIH staff will determine criteria and processes for quality control of information and data to be posted for the research community, consistent with NIH policies and achieving the goals of the program as described in this Funding Opportunity Announcement.
• Participate in recurring monthly meetings to discuss progress, obstacles and any other TC-related issues and/or activities.

The NIH will enlist additional scientific experts as necessary from within the NIH, other government agencies, such as the FDA, and from industry partners whose function will be to assist the Program Director in carrying out the goals and aims of the approved studies.

Intellectual Property

The successful development of disease models using microphysiological systems platform and the integration of these microsystems within a common platform may require either substantial investment and support by private sector industries, and/or may involve collaborations with other organizations such as academic, other government agencies, and/or non-profit research institutions not directly involved in the NIH-funded Tissue Chips Program. NIH recognizes that intellectual property rights are likely to play an important role in achieving the goals of this program. To this end, all awardees shall understand and acknowledge the following:

• The awardee is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the applicant to perform the project.
• Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the awardee to perform the project. The awardee is required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C. Sect. 202 (Bayh-Dole Act).
• Awardees are expected to make new information and materials known to the research community in a timely manner through publications, web announcements, reports to the NIH Tissue Chips Program Project Team, and other mechanisms.

Data

Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

Publications

The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the NIH Project Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee from the Cures Acceleration Network Review Board chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)

Telephone: 301-945-7573

Danilo Tagle, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064
Email: Danilo.Tagle@.nih.gov

Mohan Viswanathan, Ph.D.
National Center for Advancing Translational Sciences
Telephone: 301-312-3745
Email: mv10f@nih.gov

Esther Young
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-402-7183
Email: esther.young@nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.