Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) will support high risk/high reward research on the blood/vascular component and regulation of the neurovascular blood unit (aka. Blood-Brain Barrier; BBB) in normal and pathological states to stimulate the development of a new field of science and re-define the neurovascular unit to also include the blood/vascular component to identify targets for diagnostics and regulation of the Blood-Brain Interface. The program will also facilitate collaborations between hematologists/vascular biology experts and BBB tissue chip developers to create enhanced/modified platforms that more closely model the human BBB for assessment, as well as the development of non-invasive to minimally invasive tools to assess BBB permeability, injury, and alterations among other parameters. Research addressing vascular, hemostatic, hematopoietic, and/or immune cell interaction with the BBB is of particular interest. Applications that focus only on animal models and/or in silico predictive models of the BBB will not be responsive to the FOA. However, animal research and/or in silico predictive modeling may be used to support the development of clinically-relevant biological systems that model the human BBB. The proposed funding mechanism will include multi-PD/PI milestone-driven projects to support high risk/high reward research with the likelihood of downstream adoption for further development in collaboration with the Department of Defense (DoD) partners.

Background

To date, the role of blood in the Blood-Brain Interface (e.g., blood-derived factors, blood-based biomarkers, circulating exosomes) in the pathogenesis of neurological disorders and brain injury states (e.g., brain trauma, stroke, amyotrophic lateral sclerosis, multiple sclerosis, and Alzheimer’s Disease) and the underlying neurovascular mechanisms remain largely unknown and under-researched. A trans-agency workshop on the blood brain interface (BBI), sponsored by the National Heart, Lung and Blood Institute, the National Cancer Institute, and the Department of Defense Joint Program Committee-6 (JPC-6), Combat Casualty Care Research Program, was conducted in Bethesda MD on June 7-8, 2016. The presentations and discussions at the workshop underscored the role of the BBI in brain injury, as well as the role of the BBB as both a limiting factor and a potential conduit for drug delivery to the brain. At the conclusion of the meeting, the participants discussed challenges and opportunities confronting BBI translational researchers. In particular, the participants recommended using BBI translational research to stimulate advances in diagnostics, as well as targeted delivery approaches for detection and therapy of both brain injury and disease. This program announcement aims to address the recommendations from the 2016 Trans-Agency Blood-Brain Interface Workshop.

While other NIH-led efforts have focused on the Barrier and Brain parenchyma of the Blood-Brain Barrier, this initiative will focus on the Blood component of the Blood-Brain Barrier and the associated Interface to facilitate the development of a more complete neurovascular-blood model for translational applications with direct relevance to humans. The resulting trans-agency collaborations will also have a direct impact on future research strategies for translational medicine in this research space. NHLBI and NINDS recently convened a working group on Vascular Contributions to Cognitive Impairment and Dementia (VCID) in May 2018. The objectives of the working group were to identify research priorities that complement and expand on the VCID Research Milestones defined by the Alzheimer's Disease-Related Dementias (ADRD) Summit 2016, including those within NHLBI’s mission that will guide the field over the next 5-10 years. This initiative addresses several key challenges and recommendations from this working group including the need for molecular understanding of human brain vasculature and the BBB, assessing endothelial cell dysfunction, and characterizing the associated vascular pathology across the neuro-vascular-blood unit. While existing animal model initiatives will support new animal model development or modification of existing animal models to assess VCID mechanisms, the Trans-Agency Blood-Brain Interface Program will focus on building collaborations between hematology/vascular/circadian experts and bioengineers and tissue chip developers to create a more human like BBB model. Increased understanding of the human Blood Brain Interface will also serve as an invaluable resource for BBB researchers to develop more effective BBB assessment tools as well as validation of existing animal models.

In both health and disease, endothelial cells, neurons, pericytes, and glia constitute a neurovascular unit that regulates the BBB. Bi-directional accessibility and transport of molecules between the blood and brain are dynamically regulated in response to a number of events, such as exercise, stress, and sleep. The integrity of BBB deteriorates with age, and BBB breakdown can lead to entry of neurotoxic blood-derived products to the brain, causing inflammation, neuronal injury and neurodegeneration. Sleep-wake disturbances and circadian dysregulation can further affect the neurovascular unit and BBB integrity. Genetic risk factors for Alzheimer’s Disease (AD) together with vascular and environmental factors act on blood vessels in the brain resulting in BBB breakdown and dysfunction (e.g., faulty clearance of Amyloid beta). Changes in cerebral blood flow (CBF) following traumatic brain injury (TBI), in addition to vascular pathology, can result in BBB dysfunction. However, in addition to limiting the entry of neurotoxic plasma-derived proteins, circulating metals, red blood cells and leukocytes into the brain, the BBB also involves active cross-talk between the circulation and the nervous system. Identifying blood-derived factors which cross the blood brain interface could further facilitate translation of therapeutics in this area.

The BBB also poses a tremendous hurdle for systemic delivery of drugs to the brain. Multifunctional imaging and treatment agents utilizing nanoparticles, including extracellular vesicles (EVs), are being designed and tested to cross the BBB through receptor mediated transcytosis and to deliver drugs to brain cells efficiently and safely. There is additional evidence suggesting that BBB permeability regulation is circadian-dependent as well as sex-specific. In vitro models of the neurovascular unit allow us to elucidate the underlying physical and biochemical processes that regulate the BBB, including brain capillaries and microvessels, while simultaneously allowing us to systematically increase the complexity of the model to incorporate the blood component and generate a neuro-vascular-blood unit. Advances in BBB modeling, targeting and therapeutic delivery must also account for both normal and abnormal functions of the neuro-vascular-blood unit. Human BBB modeling will also facilitate incorporation of variables such as sex differences and circadian rhythms.

This initiative intends to take translation in this area to the next step by bringing together experts in hematology, vasculature, circadian rhythms, and BBB tissue chip development to create enhanced/modified platforms that more closely model the human BBB for assessment, as well as the development of non-invasive to minimally invasive tools to assess BBB permeability/injury/alternations among other parameters. The development of enhanced neurovascular-blood systems that will mimic the human Blood-Brain Barrier can facilitate the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to entry into clinical trials.

Research Objectives and Scope

The Trans-Agency Blood-Brain Interface Program will support innovative projects with a substantial focus on the neurovascular-blood unit (i.e., blood-brain barrier) in normal and pathological states. The intent of this FOA is to stimulate the development of a new field of blood-based science by re-defining the neurovascular unit as a component of the blood-brain interface. This will facilitate development of human-based neurovascular-blood models to identify targets for diagnostics and regulation of the blood-brain interface through multi-PI collaborations. An improved human-like BBB prototype/model can serve as an invaluable resource to the scientific community, and complement BBB research currently based on animal models.

This FOA utilizes a biphasic funding mechanism (R61/R33) to support two major consecutive experimental requirements. The first phase (R61) will focus on the development and/or the adaptation of relevant investigative models that harness the informative power of novel scientific and technologic developments (e.g., -Omics, induced pluripotent stem cells (iPSC), microfluidics, single cell analysis, or systems biology) to evaluate the role of the blood/vascular components across the Blood-Brain Interface. The second phase (R33) will seek to characterize potential mechanisms underlying human BBB function using the model(s) developed in the first phase.

The R61 phase:

The R61 Phase (1 to 2 years) is intended to support innovative applications proposing to develop or optimize a model system to examine the role of the blood/vascular components across the Blood-Brain Interface. The R61 phase will provide time for necessary preliminary work, including necessary modifications of existing approaches, methods, or technology. Successful completion of the R61 Phase will justify progression to the second phase of the project (R33). Funding for the R33 phase will be contingent upon successfully meeting the proposed R61 milestones.

The R33 phase:

The R33 Phase (up to 3 years) is intended to expand upon the developmental/exploratory work of the R61 phase with the aim of identifying and evaluating the basic cellular, molecular and physiological influence of blood and vascular components on the neurovascular-blood unit, as well as pathological processes that affect the neurovascular-blood unit, using the preclinical model(s) established in the R61 phase.

Multi-PD/PI applications representing investigators with complementary expertise in areas including but not limited to coagulation science, Omics, organ on a chip technology, inflammation, vascular biology, iPSC, hematopoietic stem cell (HSC) and niche biology, are strongly encouraged. Additionally, applicants should leverage other resources such as biospecimens and genomic sequencing data obtained from relevant clinical studies.

Proposed projects are required to include a substantial focus on the blood component of the blood-brain interface. As our understanding of the complex interactions among the various cellular and molecular components of the BBB and the interdependency of the brain and other organ systems with BBB function grows, more opportunities will reveal themselves to stimulate basic and translational research for developing new diagnostic and treatment modalities related to the neurovascular-blood unit. Areas of interest include, but are not limited to, the following:

• Development of tools for non-invasive assessment of permeability and transport across the blood-brain interface.
• Study of coagulopathy induced traumatic brain injury mechanisms and their effects on the permeability of the blood-brain interface.
• Study of neurovascular unit dysfunction and brain edema after acute TBI.
• Strategies to stabilize the BBB after TBI by limiting inflammation, neuronal injury and neurodegeneration.
• Characterization of blood-derived mechanisms regulating BBB permeability, including how BBB permeability is affected by time of day; whether BBB permeability mechanisms are sex-specific; and how the human BBB changes over the lifespan.
• The role of blood-derived factors and cross-talk mechanisms from the systemic side in BBB regulation, as well as other Blood-Brain interfaces such as the Blood-CSF interface.
• Membrane transporters can be capitalized to optimize brain exposure of potentially neuroprotective compounds in traumatic brain injury (TBI) and ischemic brain injury; repurposing transporter inhibitors/inducers can expedite clinical translation of such treatment strategies.
• Microparticle populations found in peripheral biofluid samples can be a target for assessment of post-traumatic brain injury or disease progression as well as prophylaxis or amelioration of injury progression.
• Plasma extracellular vesicles of neural origin can be the source of biomarkers and may provide a unique window for studying organ-specific cellular processes in living humans and to follow responses to experimental treatments. For example, a profile of exosomal peptides may serve as a blood test for Alzheimer’s disease (AD) and other neurological diseases.
• Nanoparticle and extracellular vesicles (EV)-based therapies can be leveraged for personalized medicine approaches at the Blood-Brain Interface.
• There are opportunities and challenges in developing the building blocks for in vitro models of the neurovascular-blood unit. . For example, iPSC-derived brain microvascular endothelial cells (BMECs) can be used as a research tool to explore drug permeability and disease at the human BBB.
• Isogenic patient-derived models of the neurovascular-blood unit can be used for biomarker identification, the study of disease progression, and therapeutic testing. Such models can also be used to test agents that selectively modulate the permeability of the blood-brain interface for drug delivery approaches.
• Patient-specific neurovascular-blood unit models may complement or replace animal models.

R61/R33 Milestones

All projects will be milestone-driven with clear go/no-go criteria that are quantifiable. Prior to funding an application, the Program Official(s) will contact the applicant to discuss the proposed R61 and R33 milestones and any changes suggested by NIH/DoD staff or the NIH review panel. The Program Official(s) and the applicant will negotiate and agree on a final set of approved R61 milestones which will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the R61 stage and progress towards interim milestones in the R33 stage. Only R61 projects that meet their milestones will have an opportunity to move to the R33 phase. R33 milestones will be the basis for judging progress towards and completion of interim milestones in the R33 stage.

Additional Considerations

Cells: The use of transformed or immortalized cell lines is discouraged, except for preliminary, proof of concept studies. The use of pluripotent stem cells, e.g., iPSC, multipotent, unipotent stem cells or genetically engineered iPSCs is encouraged. 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 selected to avoid confounding characteristics (for example, plastic polydimethylsiloxane (PDMS) binds hydrophobic drugs or reagents, which decreases the intended concentration, and can leach the endocrine disruptor cyclosilane into the medium).

Collaborations: Collaborative interactions are a critical aspect of this FOA. Model system(s) development will require extensive collaboration among hematologists/vascular experts, tissue engineering/tissue biology experts, disease experts, and clinicians.

Applications that include the following types of studies will be considered non-responsive to this FOA and will not be reviewed:

• Use of human fetal tissue for tissue chip development
• Applications that f?o?c?u?s? only on animal models ?of the BBB
• Application?s? ?t?h?a?t? f?o?c?u?s? ?o?n?l?y? on in silico predictive models of the BBB
• Engineering of non-human tissue models
• Development of simple organoid models that do not go significantly beyond those currently available and in use
• Models that do not incorporate the human blood/vascular components into the model and solely focus on the Brain-Barrier, rather than on the Blood-Brain Barrier
• Genetic / epigenetic manipulation of specific blood/vascular cells that do not entail interaction with the neurovascular tissues

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• 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 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) 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. 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.

Multi-PD/PI applications are required in response to this FOA. The research leadership team (Multi-PI PD/PI) must be comprised of experienced PDs/PIs with complementary multidisciplinary expertise for the multifaceted problems of the Blood-Brain Barrier field. If appropriate, early stage investigators or junior faculty may be included as co-investigators. The application must propose a multidisciplinary team that includes at least one team member with demonstrated expertise in blood science. Applications that do not propose a Multi-PD/PI team will be considered non-compliant and will not proceed to peer review.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide 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.

Letter of Intent

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:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.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.

R&R Budget

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, with the following additional instructions:

Specific Aims: Provide the overall goals or hypotheses for the entire project period and identify separate Specific Aims to be accomplished in the R61 phase and in the R33 phase.

Research Strategy:

• Must provide separate sections that describe both the R61 and R33 phases.
• Must provide a description of the hypothesis to be tested in the R33 phase of the study.
• Must incorporate the use of human blood/vascular components and cutting edge engineering and cell biology technologies in design of the neurovascular-blood models.
• Must provide Background and evidence of feasibility of the proposed approach.
• Must address the physiological relevance of the proposed Blood-Brain Interface model and how it can be used to assess clinically-relevant endpoints for a potential context of use.

Go/No-Go Transition Milestone for transition from the R61 Phase to the R33 Phase

• Must include a clearly identified Go/No-Go transition milestone for completion of the R61 phase at the end of Year 2 and transition to the R33 phase for 3 years of additional funding.
• A timeline (Gantt chart) including milestones must be provided for all studies. 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.

Milestones and the timeline for each stage must be provided in a separate heading at the end of the approach section for each R61 and R33 component and include the following.

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

Preliminary Data

The R61 phase will be considered exploratory, so extensive preliminary data from the applicant’s own laboratory is not required. However, the project must be based on a strong rationale, and the applicant should provide evidence that the proposed approach and methods are feasible.

Multiple PD/PI Leadership Plan

Describe plans for how the multi-PD/PIs will work collaboratively to lead the identified multidisciplinary team. Include a description of planned strategies for effective communications between and within the teams.

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.

The following modifications also apply:

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

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

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

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R61/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. A R61/R33 grant application is not required to have extensive preliminary data, background material or preliminary information, but these may be included if available. Appropriate justification for the proposed work can also be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes the R61 and R33 phases.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

In addition, specific to this FOA:

How likely is it that the proposed project will advance the understanding of neurovascular-blood unit regulation and advance the development of diagnostics and interventions? How appropriate are the overall goals to generating significant multidisciplinary investigations that respond to the overall objectives of the FOA, i.e., generating novel models for studies of the human BBB that will advance basic and translational science and/or therapy development?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

In addition, specific to this FOA:

What level of expertise and collaboration is demonstrated among the scientific fields relevant to this FOA; i.e., hematologists/vascular experts, neuroscientists, BBB tissue chip developers, disease experts, clinicians, tissue chip developers? To what extent is the leadership approach, governance and organizational structure appropriate for the project? Have collaborations been established or consultants identified to provide the appropriate depth and breadth of expertise required for the program? Is there evidence for appropriate communication and collaboration plans?

Innovation

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?

In addition, specific to this FOA:

How strong is the likelihood that the proposed R61 phase will result in the development or optimization of relevant and i?n?n?o?v?a?t?i?v?e in vivo or in vitro models that can be used to study the human neurovascular-blood unit?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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?

In addition, specific to this FOA:

How effectively is information from the Omics, iPSC, microfluidics, single cell analysis, or systems biology fields incorporated in models proposed in the R61 phase? How likely will successful completion of these milestones be relevant to the R33 phase research plans? What is the likelihood that the research proposed for the R33 phase will advance understanding of the mechanisms of BBB regulation and pathophysiology? How physiologically relevant is the proposed Blood-Brain Interface model and to what extent can it be used to assess clinically-relevant endpoints for a potential context of use?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

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?

In addition, specific to this FOA:

To what extent does the environment support the scientific fields relevant to this FOA, i.e. hematologists/vascular experts, neuroscientists, BBB tissue chip developers, disease experts, clinicians, tissue chip developers?

Milestones

Are quantitative criteria specified and clearly defined to assess milestone achievement and feasibility relevant to advancing from the R61 to the R33 phase? Are R61 milestones feasible, well-developed, appropriate, adequately described, and quantifiable with regard to the specific aims? Are quantitative threshold values specified for the proposed milestones? Specifically, to what extent will the milestones help determine if the overall project succeeded in developing enhanced/modified platforms that more closely model the human BBB by incorporating the blood/vascular component? How feasible is the study timeline ? To what extent does the application specify conditions under which they would not proceed to the R33 phase?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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.

Vertebrate Animals

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.

Biohazards

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.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

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.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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).

Resource Sharing Plans

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).

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHLBI, 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 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 National Heart, Lung and Blood Advisory Council. 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.

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information

1. Award Notices

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.

2. Administrative and National Policy Requirements

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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.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.

Not Applicable

3. Reporting

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 RPPR, 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.

Section VII. Agency Contacts

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, application errors and warnings, documenting system problems that threaten submission by the due date, and 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)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Margaret Ochocinska, PhD
Division of Blood Diseases and Research
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-827-8285
Email: ochocinm@mail.nih.gov

Marc Charette, PhD
Division of Cardiovascular Sciences
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-435-0560
Email: marc.charette@nih.gov

Marishka Brown, PhD
Division of Lung Diseases
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-435-0199
Email: marishka.brown@nih.gov

James B. (JB) Phillips, Ph.D., MBA, PMP
Neurotrauma Portfolio Manager
Combat Casualty Care, US Army Medical Research and Materiel Command (USAMRMC)
Telephone: 301-619-8079
Email: james.b.phillips10.civ@mail.mil

Nsini Umoh, PhD
Neurotrauma Portfolio
Combat Casualty Care, US Army Medical Research and Materiel Command (USAMRMC)
Telephone: 301-619-2427
Email: nsini.a.umoh.civ@mail.mil

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Kevin Heath
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8033
Email: kevin.heath2@nih.gov

Section VIII. Other Information

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.