Required Application Instructions

It is critical that applicants follow the instructions in 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

Purpose

This FOA encourages Exploratory/Developmental Research grant (R21) applications from institutions and organizations proposing research aimed at characterizing animal stem cells and improving existing, and creating new, animal models for human disease conditions for testing regenerative medicine applications. The R21 mechanism is intended to encourage innovative research projects that should break new ground or extend previous discoveries toward new directions or applications. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in well-established area, are not appropriate for R21 awards. The ORIP and representatives from other NIH institutes convened an NIH workshop in 2012 that addressed the current status of animal stem cell biology and made recommendations concerning improvements in technologies and applications of animal stem cells to regenerative medicine (see https://dpcpsi.nih.gov/sites/default/files/orip/document/summary_of_the_improving_animal_models.pdf ). The results of this workshop provide the basis for this FOA. The intent of this initiative is to facilitate the use of stem cell-based therapies for regenerative medicine. The initiative focuses on the following areas: 1) comparative analysis of animal and human stem cells to provide information for selection of the most predictive and informative model systems; 2) development of new technologies for stem cell characterization and transplantation; and 3) improvement of animal disease models for stem cell-based therapeutic applications.

Background Information

Regenerative Medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to damage or congenital defects. Regenerative medicine has the potential to solve the problem of the shortage of organs available for donation. It also holds the promise of repairing or replacing damaged tissues and organs in the body by stimulating organs previously considered irreparable to heal themselves. The recent discovery of the reprogramming of adult cells to a pluripotent state provides opportunities to address a major problem of regenerative medicine, immune rejection of transplanted tissue. The ability to generate differentiated cells and tissues using cells from specific patients will facilitate individualized medicine and eventually will lead to specialized therapies. The field is moving toward translation to clinical practice and is becoming increasingly dependent on animal models and information regarding the potential therapeutic efficacy of new technologies. Generating the correct type and quantity of the specific cell types required for replacement therapy is a significant challenge, as are the problems associated with introducing these cells into the proper environment in vivo and overcoming immune reactions. Finding solutions to these problems will require extensive testing in experimental animal models.

Major advances have been made in the past several years in deriving pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) from both humans and animals. In parallel, other investigations have isolated and characterized multipotent somatic or adult stem cells from various tissues, including Mesenchymal Stem Cells (MSCs) and Germinal Stem Cells (GSCs). The discovery of mouse ESCs in 1981 revolutionized the field of developmental biology and provided new capability for genome manipulation and investigations of gene function. Isolation of human ESCs created new possibilities for the field of regenerative medicine. ES-like cells have been derived from a number of animal species, including rats, fish, cows, pigs and non-human primates. Many characteristics of animal ES-like cells, including surface markers, growth factor requirements, ability to differentiate and others can be quite different from human ESCs. There is a continuing expansion in the number and type of stem cells which potentially can be used for stem cell therapy.

The field of stem cell research experienced a dramatic new direction with the isolation of iPSCs, derived by reprogramming somatic cells to a pluripotent state. Several studies on various animal systems suggest that the basic pluripotency network appears to be conserved among different species, allowing derivation of iPSCs from a variety of animals. Significant efforts are needed to improve reprogramming methods to generate safer iPSCs with higher efficiency and better quality.

MSCs, a type of somatic stem cell, were originally identified as a subpopulation of bone marrow cells with osteogenic potential. The properties of MSCs have been examined extensively over the past decade. Studies using animal models have shown promising results following MSC therapy for induced injury in the musculoskeletal, cardiovascular, digestive and nervous systems. In addition, many clinical trials have been initiated to test the efficacy of MSC infusion for treating various human diseases. Given the wide range of tissue sources, the recognition of subpopulations with specific properties, and the frequent production of genomic alterations upon expansion in cell culture, extensive characterization of MSCs and development of improved techniques are required. Most importantly, there is relatively limited understanding of the normal biological functions of MSCs and the mechanisms by which they participate in tissue repair.

GSCs are another type of somatic stem cell of great interest for regenerative medicine. They are an essential component of reproductive biology. Genetic manipulation of GSCs provides a powerful tool for producing transgenic animals, for elucidating mechanisms underlying germ cell development and differentiation and for understanding the interactions between stem cells and their niche. Further development of the methods for unlimited production of GSCs (for producing either sperm or eggs) will impact the ability to investigate the molecular basis of germ cell differentiation, explore the potential for germline stem cell therapy and treat infertility by transplantation. Numerous reports using animal and human GSCs have shown generation of pluripotent cells during in vitro cultivation, which potentially can solve a number of issues. However, it remains difficult to isolate, derive and maintain stable cultures of these cells from humans and model animal species. Furthermore, the mechanisms that determine the reprogramming of GSCs into pluripotent stem cells are not well understood and efficient methods for directed reprogramming of these still have to be developed.

Along with rodents, several other animal species are being developed as models for various studies in the field of regenerative medicine. Understanding the properties and capabilities of stem cells derived from animals such as fish, rabbits, dogs, pigs, sheep, goats and monkeys will increase the potential for the use of the most appropriate systems for modeling particular human disease conditions or for other medical applications. Non-rodent species, especially large animal models provide important advantages for transplantation studies, including large size, similarity to human physiology and pathology and longer life span, thus facilitating translation to studies in humans. The use of animal stem cells as a model for human cells in procedures related to regenerative medicine requires in-depth understanding of common regulatory pathways as well as species-specific properties and their impact on potential therapeutic applications.

Animal experiments have historically made a significant contribution to understanding human disease. However, animal studies need to be improved in order to increase reproducibility of the studies and better predict the effectiveness of treatment strategies in clinical trials. Several possible causes of the disparity between the results of animal studies and clinical trials have been identified, including failure to acknowledge the limitations of animal models, inadequate animal data, less than optimal disease models and overestimation of treatment efficacy due to the preferred publishing of positive results. These problems should be addressed in the design and execution of preclinical, animal-based studies involving stem-cell based therapies.

Scope of Research

The research activities specific to each of the participating Institutes and Centers (ICs) are discussed below. While the objectives of the application should be in accord with the specific interests of the ICs listed below, applications submitted for funding consideration by ORIP may be of a more general nature and should involve activities that are relevant to the interests of two or more of any of the categorical NIH Institutes and Centers. Specific interests of the sponsoring Institutes and Centers are as follows:

Projects supported by ORIP under this FOA are intended to improve existing and create new animal models for regenerative medicine. Preference will be given to investigations that examine general principles involved in developing the most informative animal models for regenerative medicine, rather than focusing on a specific disease. However, investigations involving specific diseases can be used as proof of principle. Investigations of a disease that predominantly relates to the interests of one NIH IC and peripherally relates to the interests of other NIH ICs are not appropriate for ORIP funding under this FOA. The ultimate objective of these efforts should be to provide essential preclinical knowledge that can help inform future clinical investigations.

The following are examples of research topics of particular interest to ORIP, though other innovative projects are also encouraged:

• Characterization and enhancement of animal stem cells as model systems for human stem cells. Development of innovative approaches to understand the biology of stem cells from species widely used in regenerative medicine. Rat stem cells are of particular interest, taking into account current advances in isolation and characterization of stem cells from rats, the progress of the rat genome project and current advances in the ability to manipulate rat genes.
• Development and characterization of stable, well characterized pluripotent stem cell lines from large animal species such as rabbits, dogs, pigs, goats, sheep and monkeys. Development of stem cell lines from this type of animal model should be justified as having direct relevance to potential uses in the field of regenerative medicine. Creation of biomarkers, standard protocols, species-specific reagents, proteomics, transcriptomics and genetic tools to assist the use of these cells is also of interest.
• Comparative analysis of animal and human stem cells to define criteria that will assist in choosing the most appropriate animal species and stem cell type for a particular application.
• Development of new techniques for guiding and verification of the accuracy of cell injection, tracking cell migration, evaluating off-target effects, and monitoring long-term integration and the phenotype and function of transplanted stem cells and their derivatives.
• Development of new approaches to understand and target the cell-fate-determining niche to improve extrinsic effects on stem cell function, increase cell survival and proper integration into the host environment and establish correct regulatory connections after cell-grafting experiments.
• Investigations of the therapeutic benefits of human and animal MSCs in animal models and mechanisms of their biological action. Improvement of methods for testing the efficacy and potency of MSCs in animals and for controlling the MSC secretome post-transplantation. Development of definitive markers for the multipotent state of the cells. Investigations of the cause of the high sensitivity of MSCs to the microenvironment. Standardization of culture conditions for scale up of production.
• Investigations of animal GSCs as models for understanding embryogenesis and organogenesis, stem-cell niche interactions and fate decisions. The focus should be on facilitating the application of GSCs for regenerative medicine, for example, exploring the potential for generating pluripotent cells and for deriving genetically modified animal models, including the use of haploid cells for this purpose. Preference will be given to applications working with large animal models, such as rabbits, dogs, pigs, goats, sheep and monkeys.
• Investigations to improve existing humanized animal models and create new ones. Preference will be given to studies involving species other than rodents. Of particular interest are advances in the reproducible and cost-effective generation of humanized animals, which is currently technically challenging, and development of humanized animals for in vivo generation of complex human tissues and organs using stem cells.
• Development of high throughput genetic and therapeutic screens to study stem cell biology and homeostasis in appropriate animal species, such as Drosophila and zebrafish.
• Improvement of animal disease models for regenerative medicine, which will better emulate physiological, cellular and molecular manifestations seen in humans. Development of methods to increase the predictability of stem cell based treatments in regard to effectiveness, major complications, safety and off target effects. Demonstration of the functionality of specific stem cells or their derivatives and the effectiveness of achieving specific results in improved animal disease models.
• Investigations of mammalian stem cell reprogramming and somatic cell transdifferentiation. Development of approaches and protocols for manipulating cell fate using efficient and safe methods, including removable vectors and vector systems with temporal expression of transcription factors, RNA or small molecules. Investigations regarding how these modifications can be used to control the expansion and differentiation of resident progenitor cells for direct reprogramming in vivo.
• Development of animal models for effective and sustained gene-therapy using ex-vivo engineered stem cells and their derivatives as well as endogenous stem cell populations to correct gene defects. Preference will be given to applications that provide general approaches for a broad array of uses. Applications should not be focused on therapy for specific diseases. However, a specific disease can be used as a proof of principle, if also applicable to other disease conditions. Analysis of the safety of newer technologies such as RNA-guided endonucleases (CRISPR/Cas9) and optogenetics, allowing targeted approaches for the elimination of disease-causing mutations and guided cell differentiation, as tested in animal models.
• Development of solutions to problems of stem cell therapy that have already been identified, such as heterogeneity of cell populations, genetic instability, high mutation rate during in vitro manipulations, epigenetic memory of differentiated iPSCs and immune responses induced after stem cell transplantation. Of particular interest is the development of functional assays and high-throughput techniques that will predict the potential immunogenicity of transplants and the tumorigenicity or metastatic potential of stem cell lines.
• Development of new methods or animal models to evaluate the safety of stem cell transplantation in animals, including studies of adsorption, distribution, metabolism, excretion and toxicity of stem cell-based therapeutic products. These models should take into account properties of the specific stem cell populations and should mimic the intended use of the cells in humans.

The National Institute of Dental and Craniofacial Research (NIDCR) is interested in projects that relate to the major mission of the Institute, to improve oral, dental and craniofacial health through research, research training, and the dissemination of health information. The following are examples of potential research topics, though other related innovative projects are also encouraged:

• Development of human disease- and injury-relevant animal models for tissues of oral and craniofacial complex. Projects utilizing both small and large animal models should be solicited, but preference should be given to large animal models, including humanized large animal models.
• Development and validation of predictive in vivo assays for testing safety and efficacy of tissue engineering and regenerative medicine-based therapies using clinically-relevant readouts and end-points, with a particular emphasis on assays in large animal models.
• Development of multi-prong strategies and tools for successful structural and functional integration and long-term function and survival of regenerated tissues in animal models. These include modulating disease- and injury-related infection, inflammation and tissue destruction; optimizing graft biocompatibility and preventing graft-related pathological responses; and building and rebuilding structural and functional interfaces between the regenerated and host tissues.
• Development of new strategies for regeneration of composite multi-tissues with a particular emphasis on those in large animal models.
• Validation, standardization and comparative analysis of different stem and progenitor cell sources, scaffolds and biomaterials for optimal regeneration of oral and craniofacial tissues.
• Development of efficient and controlled in vivo biomolecule-, gene- and cell-delivery strategies to tissues of oral and craniofacial complex, with a particular emphasis on delivery in large animal models.
• Development of sensitive, high-resolution in vivo cell tracking and imaging modalities as well as cell and tissue labeling and quantitative image analysis tools for tissues of oral and craniofacial complex, with a particular emphasis on live longitudinal cell tracking and imaging in large animal models.

The National Institute for Environmental Health Sciences (NIEHS) encourages applications that are relevant to the Institute's mission to determine the environmental influence on disease in order to produce preventive strategies. Research areas of interest include investigation of fundamental aspects of stem cells of all types and their role in the genesis of tumors or pre-cursors of degenerative diseases. Advances leading to improved understanding of stem and progenitor cells over the lifespan are encouraged in order to determine whether adult stem and progenitor cells behave similar to somatic cells or are more like embryonic stem cells (with respect, for example, to cell cycle regulatory mechanisms and suppression of mutations). The mechanisms of action of exposures on stem cells across the lifespan is a key to these issues and, perhaps, to individual and population susceptibility, especially at specific developmental stages. The mammary gland and the role of stem cells in breast cancer have been cited as prime areas of critical need for environmental health study and likely represent a model that could be generalizable to other cell types.

The following are examples of potential research topics, although other innovative projects are encouraged:

• Novel studies are needed to address exposures and mechanisms by which stem cell fate and function may become altered and the subsequent role in Windows of Susceptibility (WOS) the concept that cells, tissues, and individuals are more at risk from exposure at certain points in the lifelong developmental timeline. High priority will be given to investigation of the limits of WOS and the pathways by which environmental chemical exposures might initiate cells and tissues for disorders over the lifespan, including with regard to fate and lineage, population composition, tissue morphology, epigenetics, and/or DNA repair.
• The role of the environment on cellular reprogramming in pathophysiology is of interest. In particular, studies are needed on the sequence of molecular events and mechanisms (e.g. epigenetics of differentiated cells versus proliferative and reprogrammed ones under or chemically challenged conditions) in response to environmental insults.
• Engineering approaches designed to monitor and/or modify stem cell function in vivo are encouraged; such as development of novel biomaterials to serve as structures for improved control of stem cell growth, differentiation, insertion, and function with the goal of production of internal biosensors, reporters of environmental exposure, appearance of biomarkers, or toward regulatory control of stem cells for preventive or palliative strategies.

The National Institute of Allergy and Infectious Diseases (NIAID) is interested in existing animal models that have been improved or new animal models that have been developed for diseases that fall under NIAID’s mission. The Division of AIDS (DAIDS) is interested in models that support research on HIV vaccines, other prophylactic measures, therapeutics, and strategies to achieve a cure. Animal models using adult stem cell approaches with re-programmed somatic stem cells, e.g., induced pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC), are preferred for HIV/AIDS applications. DAIDS is interested in supporting the following types of research:

• Improvement of humanized mouse models using adult stem cell engraftment procedures and primate models with modified stem cells to test HIV therapy or cure strategies (The improved animal models should support testing of gene-editing approaches of human or primate stem cells or viral vector-mediated gene transfer into hematopoietic stem/progenitor cells.);
• Improved animal models for stem cell-based regenerative medicine approaches to reprogram or restore immune functions in HIV-infected patients; and
• Development of stem cell-based humanized animal models for HIV vaccine research that reflect human immune responses and are predictive of HIV vaccine efficacy in humans.

The Division of Allergy, Immunology and Transplanation (DAIT) supports basic and clinical research to understand normal immune system function, determine the causes of immunologic diseases, and develop better diagnostic, treatment, and prevention strategies for these diseases. DAIT also coordinates and administers the National Institutes of Health effort to develop new medical countermeasures against radiological and nuclear threats. Through this Funding Opportunity Announcement, DAIT is interested in supporting:

• Development of new approaches to improve engraftment, tissue homing, and function of stem cells to promote successful immune system reconstitution and thymic regeneration in animal models, including methods to induce development of non-lymphoid and lymphoid cells from reprogrammed stem cells, and improved humanized animal models (rodent and large animal) of immune reconstitution;
• Investigations and development of models to elucidate the role of HSC and/or MSC transplantation as a tolerogenic adjunct to organ or pancreatic islet transplantation;
• Development of approaches to prevent an alloimmune response to transplanted cells or tissues derived from iPSC or ESCs; and
• Investigation and development of the use of stems cells for mitigation and/or treatment of radiation injuries following a radiological/nuclear incident.

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:

• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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) (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).

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in 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.

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.

In addition, provide the following information:

Proves of appropriate training and expertise of the PD(s)/PI(s) to conduct studies of animal stem cells and their comparative analysis to human stem cells. Address the issue of the sufficient expertise of the corresponding human disease condition presented in the research team if a creation or improvement of existing disease models is proposed.

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:

Research Strategy: Provide the following information.

• Description of the gaps in knowledge regarding properties of stem cells of specific animal species and in understanding their similarities and differences in comparison to human stem cells which this studies will address.
• A statement which will describe how this project will facilitate the use of stem cells in regenerative medicine applications.
• Describe innovations to solve potential challenges of stem cell therapy as well as approaches to rapidly provide the project data and resources to biomedical community the project will utilize.
• If cell lines, reagents or other biomaterials are developed, the applicant must specify how duplicate storage facilities will be maintained so that these materials will not be lost in case of natural disaster. If new strains of animals are developed, the applicant must specify how germ plasm will be cryopreserved and stored in duplicate facilities.

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 Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants are required to follow our Post Submission Application Materials policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

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? In addition to the standardized criteria above, the following will be evaluated as part of the significance score. Will the proposed studies address gaps in knowledge regarding properties of stem cells of specific animal species and in understanding their similarities and differences in comparison to human stem cells? Will the project facilitate the use of stem cells in regenerative medicine applications?

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 to the standardized criteria above, the following will be evaluated as part of the Investigator(s) score. Are the PD(s)/PI(s) appropriately trained and well suited to conduct studies of animal stem cells and, if suggested, their comparative analysis to human stem cells? If creation of new or improvement of existing disease models is proposed, is there sufficient expertise of the corresponding human disease condition represented in the research team?

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 to the standardized criteria above, the following will be evaluated as part of the Innovation score. Will the proposed studies help to find innovative solutions to potential challenges in stem cell therapy? Does the application utilize innovative approaches to rapidly provide the project data and resources to the biomedical community? Is the technology development aspect of the application innovative?

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? In addition to the standardized criteria above, the following will be evaluated as part of the Approach score. Are adequate approaches proposed for enhancement of the capacity to utilize innovative technologies and improve the efficiency of generating well characterized animal stem cells? Will the proposed studies lead to increasing the predictive validity of animal models for regenerative medicine? Is sufficient information provided concerning selection of the most appropriate and predictive disease, if such studies are proposed?

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? In addition to the standardized criteria above, the following will be evaluated as part of the Environment score. Is there appropriate Institutional Support for the project, and are plans for continuity appropriate for the scientific field’s needs?

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.

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.

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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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 the Center for Scientific Review, 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 be discussed and assigned an overall impact score.
• Will receive a written critique.

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 . Following initial peer review, recommended applications will receive a second level of review by the appropriate NIH 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.

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.

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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://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 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 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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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.

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: https://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 CenterTelephone: 800-518-4726
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

Oleg Mirochnitchenko, Ph.D.
Office of Research Infrastructure Programs (ORIP)
Telephone: 301-435-0748
Email: oleg.mirochnitchenko@nih.gov

Nadya Lumelsky, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-7703
Email: nadyal@nidcr.nih.gov

Les Reinlib, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-4998
Email: reinlib@niehs.nih.gov

Brigitte Sanders, DVM, PhD, RAC
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3209
Email: Brigitte.Sanders@nih.gov

Alison Deckhut Augustine, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3475
Email: augustine@niaid.nih.gov

Maqsood A. Wani, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-2770
Email: mw486e@nih.gov

Nyron Rouse
National Center for Advancing Translational Sciences (NCATS)
Office of Research Infrastructure Programs (ORIP)
Telephone: 301-435-0840
Email: rousenm@mail.nih.gov

Dede Rutberg
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: dr258t@nih.gov

Aaron Nicholas
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-7823
Email: nicholaa@mail.nih.gov

Donna R. Sullivan
National Institute of Allergy and Infectious Disease (NIAID)
Telephone: 240-669-2979
Email: ds488d@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.