Expired PAR-13-252: Improvement of Animal Models for Stem Cell-Based Regenerative Medicine (R24)

Part 1. Overview Information

Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP) National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	Improvement of Animal Models for Stem Cell-Based Regenerative Medicine (R24)
Activity Code	R24 Resource-Related Research Projects
Announcement Type	Reissue of PAR-13-113
Related Notices	June 13, 2016 - This PAR has been reissued as PAR-16-322. NOT-OD-16-004 - NIH & AHRQ Announce Upcoming Changes to Policies, Instructions and Forms for 2016 Grant Applications (November 18, 2015) NOT-OD-16-006 - Simplification of the Vertebrate Animals Section of NIH Grant Applications and Contract Proposals (November 18, 2015) June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.
Funding Opportunity Announcement (FOA) Number	PAR-13-252
Companion Funding Opportunity	PAR-16-094, R21, Exploratory/Developmental Research Grant PAR-16-093, R01, Research Project Grant PAR-13-114, R01, Investigator Initiated Research Project Grants PAR-13-115, R21, Exploratory/Development Grants
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.351, 93.855, 93.856
Funding Opportunity Purpose	This FOA encourages Resource-Related Research Project Grant (R24) 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. 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.

Key Dates

Posted Date	July 3, 2013
Open Date (Earliest Submission Date)	August 25, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	New Date June 13, 2016 per issuance of PAR-16-322. (Original Expiration Date: September 8, 2016)
Due Dates for E.O. 12372	Not Applicable

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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This FOA encourages Resource-Related Research Project Grant (R24) 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. The Division of Comparative Medicine (DCM) in ORIP 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. 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 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.

The field of stem cell research experienced a dramatic new direction with the isolation of iPSCs, derived by reprogramming human or mouse 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.

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 demonstrated 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 cells 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 and for treatment of 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 rabbits, 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 (often referred to as 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 better predict the efficacy 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 and conclusions from them, 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.

Research Objectives

The research activities specific to each of the participating Institutes and Centers (ICs) are discussed below.

Projects supported by ORIP/DPCPSI under this FOA are intended to improve existing and create new animal models for regenerative medicine. Efficient use of animal models is facilitated by development of specific resources for characterizing, archiving and distributing animals as well as research tools, reagents and stem cell lines of utility to research on a variety of animal species. Development of an animal-based resource often requires preliminary work that is research-based. This resource-related research is often not hypothesis driven and cannot be addressed appropriately by NIH R01 or R21 grant applications. Accordingly, ORIP/DPCPSI supports R24 grants which have the following features:

The grants support applied studies to characterize and develop new animal based resources or to improve existing resources.
The grants support research projects that contribute to the knowledge of a model system, making the system more useful and accessible to the research community.
In all cases, the potential results of investigations must be applicable to the interests of two or more of the NIH categorical Institutes and Centers (ICs). Furthermore, investigations of a disease that predominantly relates to the interests of one NIH categorical IC and peripherally relates to the interests of other NIH ICs are not appropriate for this FOA. 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. An example of an inappropriate request is one exclusively involving an animal model of cancer. The ultimate objective of these efforts should be to provide essential preclinical knowledge that can help inform future clinical investigations.
The particular emphasis of a specific R24 application can vary in regard to the balance of research- versus resource-related activities, depending on the state of the art at the time. An R24 grant application can be predominantly research based, if the research will plausibly lead to development of a resource, or can be predominantly aimed at final development or enhancement of a resource if most of the necessary research has already been accomplished.
The R24 grant application must demonstrate a need for the resource (or resource to be developed) by the biomedical research community.
Cost recovery is not required.

The following are examples of research topics of particular interest to ORIP. Other innovative projects are also encouraged:

Characterization and enhancement of animal stem cells as model systems for human stem cells. 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, 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.
Redirection of existing or creation of new national centralized facilities with robust capacity to purify, characterize and store stem cells from large animal species for regenerative medicine applications, to maintain databases and make biomaterials available to the wide biomedical community as well as to develop and produce isogenic lines.
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; 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 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, 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 chimeras, which is currently technically challenging. 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 and distribution of the reagents, protocols, stem cell lines, vectors, genetically altered animal strains and disease models, suitable for such screening.
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. Further 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. Improvement and investigations of the safety of newer technologies such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), allowing targeted approaches for the elimination of disease-causing mutations, 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.
Development of public databases that will contain information on: Reproducible experimental conditions; Cell lines and related biomaterials; Results of testing animal and human stem cells in animal models, and; Cross-species and unique phenotypes that will assist future biomedical scientists and medical practitioners in the selection of the most relevant pre-clinical model.

The National Institute of Allergy and Infectious Diseases (NIAID) is interested in applications that are relevant to the Institute s mission, i.e., conduct and support basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases. Of particular interest are projects within these disease areas focused on:

Gene-editing of stem cells, delivery of lentiviral vectors encoding antiviral genes or therapeutic substances to stem cells, and genetic modification of stem cells from other sources than the usual CD34+ hematopoietic stem cell, e.g., induced pluripotent stem cells (iPSC), embryonic stem cells, or other type of stem cells.
Humanized mouse models using engraftment procedures and animal models to develop new HIV therapies or Cure strategies
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

Section II. Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 4 years.

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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Required Registrations

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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

Eligible Individuals (Program Director/Principal Investigator)

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.

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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download 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.

2. Content and Form of Application Submission

It is critical that applicants follow the 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.

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

Page Limitations

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

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

SF424(R&R) Cover