CHARACTERIZATION, BEHAVIOR AND PLASTICITY OF PLURIPOTENT STEM CELLS RELEASE DATE: May 4, 2004 PA NUMBER: PA-04-101 The R01 portion of this funding opportunity has been replaced by PA-07-201, which now uses the electronic SF424 (R&R) application for February 5, 2007 submission dates and beyond. March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through using the electronic SF424 (R&R) application. Accordingly, this funding opportunity expires on the date indicated below. A replacement R21 (PA-06-198) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates thereafter. See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and AIDS-related R03 and R21 Applications. Expiration Date for R21 Non-AIDS Applications: March 2, 2006 Expiration Date for R21 AIDS and AIDS-Related Applications: May 2, 2006 Expiration Date for R01 Non-AIDS Applications: November 2, 2006 Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) ( COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute of Neurological Disorders and Stroke (NINDS) ( National Institute on Deafness and Other Communication Disorders (NIDCD) ( National Institute on Aging (NIA) ( National Institute of Child Health and Human Development (NICHD) ( National Cancer Institute (NCI) ( National Institute on Drug Abuse (NIDA) ( National Institute of Mental Health (NIMH) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: NINDS 93.853, NIDCD 93.173, NIA 93.866, NICHD 93.929, NCI 93.396, NIDA 93.279, and NIMH 93.242. THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE Stem cells appear to possess great plasticity, but the cellular mechanisms regulating their behavior and fate are not understood. If these mechanisms can be harnessed to obtain cells specifically required for therapy, diagnosis or drug discovery, it may be possible to restore function to tissues and organ systems that have been compromised by congenital disorders, developmental malfunction, age, injury, disease or drug exposure. The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Deafness and Other Communication Disorders (NIDCD), the National Institute on Aging (NIA), the National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute of Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH) invite applications for studies on the characterization, behavior and plasticity of human and non-human stem cells, regulation of their replication, differentiation, integration and function in the nervous system, and the identification and characterization of normal and tumor stem cells. An understanding of intrinsic and extrinsic signals, especially those involved in the stem cell niche, age-dependent processes and genetic factors that govern the activities of pluripotent cells is crucial in order to utilize them to develop safe and effective treatments for the restoration of function, or to prevent their transformation into tumor-generating cells. Although animal studies demonstrate that stem or progenitor cells can be derived from a variety of tissues and from hosts of different ages, the requirements and potential for differentiation of each type of pluripotent cell appear to be unique. We lack a clear understanding of the intrinsic properties that distinguish one population from another, and how these populations differ in their response to similar conditions in vitro and in vivo. This Program Announcement, which replaces PA-01-078 (Biology of Non- Human Stem Cells in the Environment of the Nervous System) and PA-02-025 (Plasticity of Human Stem Cells in the Nervous System), encourages applications to study the fundamental properties of all classes of human and non-human stem cells, and to confirm, extend, and compare the behavior of stem cells that are derived from different sources and ages or exposed to different regimes in vitro and in vivo or derived from tumors. Of high priority are studies to develop methods for identifying, isolating and characterizing specific precursor populations at intermediate stages of differentiation into neurons and glia, and their relationship to tumor- generating cells. Projects that address comparisons between different classes of human stem cells and between human and non-human stem cells would also be directly relevant to this PA. RESEARCH OBJECTIVES Background Stem cell research offers enormous potential for treating a host of congenital, developmental, psychiatric or degenerative diseases for which there are no cures. In animal studies, multipotent progenitor cells from many different sources have been reported to generate cells with neuronal or glial properties, raising expectations that they could be used to replace lost neurons and glia, repair defective circuits, and restore functions compromised by abnormal development, age, physical damage, disease or drug addiction. In addition to cell and tissue therapy, the ability to selectively produce one or more differentiated cell types at will from pluripotent stem cells would be of clinical importance in investigating the effects of drugs, environmental and genetic factors on differentiation and cell function in the human nervous system. These approaches could aid in the discovery of drugs and ultimately in the development of a variety of effective treatment strategies. Major challenges have to be overcome before any type of stem cell can be harnessed and translated to meaningful treatments for patients. These challenges include identifying the optimal type of stem cell or stem cell derivative for specific assays and therapies for individual disorders, harvesting and growing sufficient quantities of the appropriate cell type, deciding the best therapeutic strategy for each condition to be treated, and assessing the potential side effects that may arise when such versatile cells are introduced into a patient. In addition, examples of the enormous plasticity exhibited by stem cells raise fundamental questions about the comparative potential for differentiation of precursor cells derived from different sources and different stages of development, the nature of the conditions that regulates stem cell behavior, and the genetic, molecular and cellular mechanisms that result in functional integration within the nervous system over the lifespan of the host. Of the many types of progenitor cells competent to develop neuronal and glial features, embryonic stem (ES) cells, derived from embryos at the blastocyst stage, may have the broadest natural potential for differentiation because, during development, they normally produce all the cells of an organism. These pluripotent cell lines are characterized by nearly unlimited self-renewal and differentiation capacity. During differentiation in vitro, mouse and human ES cells express properties of mature tissues such as muscles, several classes of neurons, glia, pancreatic islet cells, cartilage and blood. When transplanted into the central nervous system (CNS), ES cells that have been coaxed along an oligodendrocytic lineage will form myelin and ensheath axons. Some improved function was reported in rodent models of demyelination and spinal cord injury that received these ES cell-derived transplants. However, how the transplanted cells contributed to the restoration of function is unclear. Other sources of progenitors are neural stem cells that are derived from neurogenic regions in the developing and adult CNS. They integrate seamlessly into the host when transplanted into the developing nervous system, but their fate appears highly dependent upon the local environment that they encounter. This is particularly true when these cells are introduced into the adult CNS. For example, cells that can become neurons in one part of the nervous system, such as the hippocampus, generate astrocytes exclusively when placed into the spinal cord. The concept of the niche has emerged recently as an important one; yet at the present time, we have very little information on the nature of the environmental signals that regulate fate decisions of stem cells. Of particular interest are recent reports from a number of investigators that stem cells present in adult, non-neuronal tissues appear to show surprising plasticity or versatility. For example, under specific culture conditions, bone marrow stromal cells appear to trans-differentiate to give rise to cells with neuronal or glial features. Following bone marrow transplantation, donor-derived cells could be found in many tissues including the CNS, skeletal muscle, liver, heart, vascular endothelia, and bone. Some of these findings have been attributed to the fusion of a donor cell with a mature host cell, giving the appearance of trans-differentiation of the donor cell to an unrelated adult phenotype. Other reports of switches in lineage cannot be explained by fusion. Perhaps most intriguing is the hypothesis that cells committed to a particular lineage may de-differentiate to a more pluripotent state. One of the most attractive sequelae of plasticity is the possibility of developing autologous cells for transplantation, because autologous grafts will not be rejected by the host or recipient. On the other hand, the pliable nature of stem cells raises the concern that transplanted cells could be triggered by the local environment to an undesired phenotype with unpredictable consequences. Before we can design therapies using human stem cells, we must understand how "plastic" or malleable are these different classes of cells, the signals that drive their choice of fates, and how reversible are these fates. For unknown reasons, select populations of cells are destroyed in specific neurological disorders and diseases - dopaminergic neurons in Parkinson's Disease (PD), cholinergic neurons in Alzheimer's Disease(AD), motor neurons in Amyotrophic Lateral Sclerosis (ALS) and myelinating oligodendrocytes in Multiple Sclerosis (MS). Because there is great diversity of neurons and glia, studies to develop treatments for these and other diseases with less well defined etiologies will require the characterization and acquisition of unique populations of neurons and glia. While dopaminergic neurons are clearly the target of studies on PD, defining the specific features of the dopaminergic neurons needed to treat PD is less obvious. Each neuronal and glial phenotype is defined by a constellation of morphological, biochemical, genetic, and electro-physiological properties, and the functional significance or impact of a neuronal population depends on connectivity with appropriate afferent and efferent populations. It is necessary to determine the optimal stem cell and protocol that will produce a differentiated phenotype that best replicates the significant properties required and can replace the dysfunctional cell type. The features most commonly evaluated include morphology, biochemical and gene expression, and physiology. Less often described are quantification of protein and gene levels, acquisition and maintenance of phenotype over time, cell division and migration, and the simultaneous tracking of multiple properties in a population of cells. Least studied are the integration and functional consequences of the transplanted cells in the host, and the long-term behavior of the transplanted population. In summary, because we know little about the biology and the comparative scope for differentiation of the many different types of stem cells, it is difficult to assess realistically their potential for use in developing treatments for neurological disease and other conditions. Recent findings demonstrate that in select regions of the avian and mammalian nervous systems, endogenous neural stem and precursor cells continue to produce new neurons and circuits throughout adulthood, and indeed over the entire lifespan, though new cell production declines with age. In the adult hippocampus, newly born neurons acquire the size and morphology of their older neighbors and establish contacts with existing circuits in the brain, a process that can take months to complete. Endogenous stem cells can replace hair cells of the inner ear following acoustic and drug-induced damage in the adult avian and amphibian nervous systems. Similarly, the sensory neurons of the olfactory epithelium are replaced on a regular basis, and especially in response to injury, from an endogenous stem cell pool. Behavior, experience and drugs such as anti-depressants have demonstrable and profound effects on the production and establishment of new neurons in the adult and the aging brain. Drug abuse, on the other hand, have been shown to inhibit neurogenesis in rodents and result in developmental deficits and cognitive dysfunctions in humans and animals. All these findings have important implications for development, learning, memory and the maintenance of a healthy nervous system that functions throughout life. New research into mechanisms that influence ongoing neurogenesis and gliogenesis will provide fundamental information on the capacity of the nervous system to adapt in response to pharmacological and behavioral therapy throughout life. The hope is that processes that regulate the native production and integration of new neurons may be deployed to repair disordered regions of the brain. Objectives and Scope This Program Announcement is intended to promote studies of stem cell biology and the regulation and control of stem cells in the nervous system. Research efforts on characteristics that distinguish between different types of stem cells and the cellular, molecular and genetic mechanisms that influence their lineage choices are particularly relevant, as are studies that explore the long-term fates of stem cell-derived populations in animal models. Also of interest is the development of methods for isolating specific cell populations, and studies that demonstrate or enhance the safety of stem cells in treatments for neurological conditions. The following examples illustrate areas that are of high interest; other innovative projects are also encouraged. o Comparison of the mitotic potential and fates of different types of pluripotent, progenitor cells in vitro and in vivo. o Comparison of the migratory properties and structural and functional integration of different types of progenitor cells in the developing, adult or aging host nervous system. o Comparison of the behavior of human stem cells with that of their non- human counterparts in vitro and in vivo. o Investigation of the ability of different types of stem cells or of partially differentiated cells to revert to a more plastic, multipotent state, under normal conditions and following injury, disease or drug exposure. o Examination of changes in gene and protein expression as human and animal stem cells differentiate along specific lineages. o Identification of signals, signaling pathway components and transcriptional factors that regulate the fate(s) of transplanted stem cells and their progeny in the nervous system of the host. o Development of markers and assays (in vitro and in vivo) that permit accurate and reliable characterization of the state of differentiation of human and non-human stem or neural precursor cells. o Development of methods for identifying, isolating and enriching select precursor populations, intermediate states, and differentiated neuronal and glial phenotypes. o Development of a public database of gene expression patterns for human and non-human stem cells as they self-renew or develop and mature into specific neuronal and glial fates. o Use of animal model systems of neurological and neuropsychiatric disorders and of drug addiction for screening and comparing the functional capabilities of implanted stem cells and their progeny. o Assessment of the ability of transplanted cells to integrate with the adult and aging host nervous system and modify dysfunctional states. o Assessment of the long-term fates and the consequences of transplanted cells and their progeny in the nervous system, and in ectopic sites within the host. o Assessment and comparison of the immune responses generated by different human stem cells and their progeny in the host. o Assessment of the behavior of host cells in response to the short-term and long-term presence of transplanted human stem cells and/or their derivatives. o Comparison of the efficacy and risks of different modes of cell delivery in large and small mammals, and in animals of different ages. o Development of novel techniques such as non-invasive methods to track the location, phenotype, integration and/or function of transplanted stem cells and their progeny. o Assessment of the effects of environmental changes, therapies, or rehabilitation strategies on the production, differentiation and survival of endogenous stem cells across the lifespan. MECHANISM OF SUPPORT The Exploratory/Developmental Grants (R21) mechanism and the Research Project (R01) grant mechanism will be used to support projects under this Program Announcement (PA). Under these mechanisms, responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The proposed project period during which the research will be conducted should adequately reflect the time required to accomplish the stated goals and should be no more than 5 years for R01 grants. The R21 mechanism (see is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. These one-time awards support innovative, high impact research projects that 1) assess the feasibility of a novel area of investigation or a new experimental system, 2) include the unique and innovative use of an existing methodology to explore a new scientific area, 3) involve considerable risk but may lead to a breakthrough in a particular area, or 4) develop new technology or methodology that could have major impact in a specific research area. 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 a well- established area will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications. R21 applications may request a project period of up to two years with a combined budget for direct costs of up to $275,000 for the two year period. For example, you may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of your project. Normally, no more than $200,000 may be requested in any single year. For further information on the R21 mechanism, including Institute-specific information,see This PA uses just-in-time concepts. It also uses the modular budgeting as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format. Otherwise follow the instructions for non-modular budget research grant applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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 programs. SPECIAL REQUIREMENTS Use of human embryonic stem cells (hESCs): Criteria for federal funding of research on hESCs can be found at All cell lines that meet these criteria and are therefore eligible for research with federal funding are identified and registered in the NIH Human Embryonic Stem Cell Registry ( NIH has established a website ( that provides information in the form of answers to frequently asked questions about implementation issues for human embryonic stem cell research (see also: Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for funding. Each approved cell line is specifically identified by an NIH code in the Registry. It is the responsibility of the applicant to provide in the Description (page 2) of their application the official NIH identifier(s) for the hESC line(s) that they will use as found in the NIH Registry ( Applications that do not provide this information will be returned without review. Plan for Dissemination of Data and Biomaterials: Sharing of biomaterials, data, and software in a timely manner is essential for rapid progress in biomedical research. All applicants who respond to this PA must propose plans for sharing data and biomaterials generated through the grant. PHS policy requires that investigators make unique research resources available for research purposes to qualified individuals within the scientific community when they have been published (see the NIH Grants Policy Statement at In addition, NIH recently released a statement on the sharing of research data that applies to all investigator-initiated applications with direct costs greater than $500,000 in any single year ( The Initial Review Group will evaluate the proposed sharing plan and comment on its adequacy in an administrative note in the summary statement. Reviewers will not factor the proposed data-sharing plan into the determination of scientific merit or priority score. The adequacy of the plan will be considered by NIH staff in determining whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Arlene Y. Chiu, Ph.D. Program Director, Repair and Plasticity Program National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2206, MSC 9525 Bethesda, MD 20892-9525 Telephone: (301) 496-1447 FAX: (301) 480-1080 Email: Barry J. Davis, Ph.D. Division of Scientific Programs NIDCD / Suite 400C 6120 Executive Blvd., MSC 7180 Rockville, MD 20892-7180 Phone: 301-402-3464 FAX: 301-402-6251 Email: Bradley C Wise, Ph.D. Program Director, Fundamental Neuroscience Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 350 7201 Wisconsin Avenue MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: Ralph M. Nitkin, Ph.D. Biological Sciences and Career Development Program National Center for Medical Rehabilitation Research National Institute of Child Health and Human Development Executive Building, Room 2A03 6100 Executive Blvd, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 402-4206 FAX: (301) 402-0832 Email: Neeraja Sathyamoorthy, Ph.D. Program Director Tumor Biology & Metastasis Branch Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard EPN 5036 Rockville MD 20892 Phone: 301-435-1878 Fax: 301-480-0864 Email: Geraline C. Lin, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 435-1305 FAX: (301) 594-6043 Email: Beth-Anne Sieber, Ph.D. Chief, Developmental Neurobiology Program National Institute of Mental Health Division of Neuroscience and Basic Behavioral Science 6001 Executive Boulevard, Rm 7186 Bethesda, MD 20892-9641 Phone: (301) 443-5288 Fax: (301) 402-4740 E-mail: o Direct your questions about financial or grants management matters to: Michael J. Loewe Chief, Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Suite 3290, MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: Or to Gavin Wilkom Grants Management Specialist Grants Management Branch, DER National Institute of Neurological Disorders and Stroke Neuroscience Center, 6001 Executive Blvd. Room 3250, MSC 9537 Bethesda MD, 20892 Telephone: (301) 496-7480 FAX: 301-402-0219 Email: Sara Stone Chief, Grants Management Office Division of Extramural Activities NIDCD / Suite 400B 6120 Executive Blvd, MSC-7180 Bethesda, MD 20892-7180 Telephone: (301)402-0909 FAX: (301) 4021758 Email: Linda Whipp Grants Management Officer Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212 MSC9205 Bethesda, Maryland 20892-9205 Telephone: (301) 496-1472 Chris Robey Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6996 FAX: (301) 451-5510 Email: Bill Wells Grants Administration Branch National Cancer Institute EPS Room 243 6130 Executive Boulevard Rockville MD 20892 Phone: 301-496-8796 Email: Diana Haikalis Acting Team Leader Grants Management Branch National Institute on Drug Abuse 6101 Executive Boulevard Room 270 MSC 8403 Bethesda, MD 20892-8403 Telephone: (301) 443-6710 Email: Rebecca Claycamp, CRA Chief Grants Management Officer National Institute of Mental Health 6001 Executive Boulevard, Room 6122, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2811 FAX: (301) 443-6885 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Description (page 2) The NIH identifier(s) of the hESC line(s) to be used must be included. o Research Plan For R21 applications only, items a d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required for R21 proposals, but may be included if it is available. Please note that a Progress Report is not needed for R21 awards; competing continuation applications for an exploratory/developmental grant will not be accepted. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that for R21 applications, no more than 5 manuscripts, previously accepted for publication, may be included. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget grant format. The modular budget grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an unfunded version of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures ( will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the appropriate national advisory council or board REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to evaluate application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS Sharing Research Data Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their application. The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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