STEM CELL RESEARCH FOR ALCOHOL-RELATED DISORDERS Release Date: March 13, 2002 RFA: RFA-AA-02-010 National Institute on Alcohol Abuse and Alcoholism (NIAAA) (http://www.niaaa.nih.gov) LETTER OF INTENT RECEIPT DATE: April 15, 2002 APPLICATION RECEIPT DATE: May 15, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this RFA is to foster research on 1) the impact of alcohol exposure on embryonic and adult stem cell biology, 2) the capacity of stem cells to replace tissues and/or restore function directly at sites of alcohol- induced organ and fetal damage in animal models, 3) the use of stem cells as a tool to further elucidate mechanisms of alcohol dependence and alcohol-related pathological conditions, such as brain degeneration, alcoholic liver disease, pancreatitis, and fetal alcohol syndrome, and 4) restoration of normal function in alcohol-damaged tissues using stem cells in combination with gene therapy. RESEARCH OBJECTIVES Background Long-term alcohol abuse is known to cause pathologies in a number of the body"s organ systems. Those disorders most commonly associated with chronic alcohol consumption include alcoholic liver disease (ALD), pancreatitis, cardiovascular disease, endocrine dysfunction, osteoporosis, cancer, and immune dysfunction. Heavy alcohol intake is also associated with structural and functional changes in the adult and developing central nervous system, manifested by brain atrophy and neurodegeneration, as well as neurodevelopmental disorders such as fetal alcohol syndrome. Brain regions most severely affected by chronic alcohol consumption, as well as by prenatal alcohol exposure, are the frontal cortex, cerebellum, hippocampus, and the hypothalamus. Embryonic and adult stem cells offer powerful tools to elucidate mechanisms underlying normal biological functions and the mechanisms by which alcohol disrupts normal functions in susceptible organs. They may also prove valuable in developing therapeutic approaches for treating alcohol-induced physiological impairments and overt organ damage. Although rapid progress has been made in characterizing embryonic and adult stem cells and their capacity to proliferate, migrate, differentiate, and integrate into multiple tissues, very little is known about how alcohol affects these processes. For example, does alcohol exposure alter normal stem cell fate determination and plasticity? Does chronic alcohol consumption alter the number and availability of autologous stem cells and their biological properties? Does alcohol exposure alter the biochemical environment of tissues, thus interfering with the capacity of stem cells to establish contact, differentiate and function in target tissues? Does alcohol interfere with the capacity of endogenous stem cells to limit or repair alcohol-induced pathology in various tissues? These are some of the fundamental research questions that need to be addressed. It now appears that cell fate changes are a natural property of stem cells and may be involved in tissue homeostasis and repair of tissue damage. For example, adult neural stem cells have the capacity to express a variety of neuronal cell types, and hematopoietic stem cells have been shown to form functional liver hepatocytes. Evidence suggests that circulating stem cells home to niches within an organ, where signaling factors stimulate differentiation into the desired cell types. The effects of different patterns of chronic alcohol exposure on the niche environments essential for engrafting and differentiation of stem cells needs further investigation. Although more research is needed to improve stem cell isolation techniques, use of autologous adult stem cells for tissue-replacement therapy could represent a major advantage by avoiding immune rejection. However, it is unclear whether chronic alcohol consumption would also destroy the host"s natural supply of stem cells and/or alter their capacity to respond to cellular signals in target tissues. In liver regeneration, both oval stem cells and hematopoietic stem cells are key players, thus, the capacity of these cells to regenerate the architecture necessary to support liver function after chronic alcohol exposure also needs to be studied. Stem cells have particularly exciting potential in combination with genetic engineering strategies and gene therapy. Stem cells stably expressing transgenes may be used to deliver soluble molecules to specific sites by migrating and differentiating into the target tissue. In addition to tissue repair, stem cells have the potential to control progression of disease. For example, engrafted stem cells engineered to overexpress proteins in specific brain regions potentially could modulate host levels of critical neurotransmitters involved in pathological alcohol consumption. Furthermore, transgene expression in a patient"s own somatic stem cells should prevent the adverse immune responses often seen with adenovirus and other gene therapy vectors. Combination therapy is likely to be most useful for certain alcohol- related disorders where delivery of genes will compensate for impaired enzymes, peptides, and neurotransmitters. Research Objectives and Scope This RFA solicits research on the application of stem cells to alcohol- relevant problems. The use of stem cells derived from any approved source, including human embryonic stem cell lines listed in the NIH Human Embryonic Stem Cell Registry (see REQUIRED FEDERAL CITATIONS below for additional information) is encouraged. Although some types of clinical research would be appropriate for this RFA, clinical trials are outside the scope of the RFA. Examples of research that would be responsive to this RFA are identified below. These research areas are not intended to be inclusive or restrictive. o Studies on the effects of alcohol on in vivo and ex vivo stem cell viability and differentiation into specific cell types including neurons,glial cells, liver cells, pancreatic cells, cardiomyocytes, etc. o Biochemical and physiological studies examining the capacity of stem cells to integrate with host tissues and to restore impaired tissue function under conditions of chronic alcohol exposure. o Studies to determine the effects of alcohol dose and exposure pattern on the long-term fate of transplanted stem cell-derived populations in animal models of alcohol-induced tissue injury including brain and liver damage. o Studies to assess the functional integrity of autologous stem cells in animal models of prenatal, adolescent, and adult alcohol exposure. o Studies to determine the effectiveness of stem cells engineered to overexpress candidate genes/proteins to offset/reverse neural maladaptive responses to alcohol, such as tolerance, dependence, craving, and withdrawal. o Development, in animal models, of stem cell transplantation and combination stem cell/gene therapy approaches to protect against or prevent alcohol- induced tissue damage, or hasten repair of integral processes that are sensitive to alcohol. MECHANISM OF SUPPORT This RFA will use NIH research project grant (R01), NIAAA exploratory/developmental grant (R21), and NIAAA small grant (R03) award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. Exploratory/developmental grants (R21) are limited to three years for up to $100,000 per year for direct costs. (See PA-99-131, "NIAAA Exploratory/Developmental Grant Program," http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete description of the R21 mechanism.) Small grants (R03) are limited to two years for up to $50,000 per year for direct costs. (See PAR-99-098, "NIAAA Small Grant Program," http://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html, for a complete description of the R03 mechanism.) This RFA is a one-time solicitation. Future unsolicited, competing applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $300,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE The NIAAA intends to commit approximately $2 million in FY 2002 to fund six to eight new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $300,000 per year, using the R01 support mechanism. An applicant may request a shorter project period and lesser amount of support, using the R03 or R21 mechanism, as described above. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIAAA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit an application 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 (only domestic organizations are eligible for the R03 mechanism) 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 Investigators wishing to obtain support for research relevant to this RFA who lack expertise in alcohol research are encouraged to collaborate with investigators who are experienced in alcohol research, insofar as such experience will prove essential for proper study design and data analysis. Investigators desiring to establish such collaborations are encouraged to contact the individuals listed under WHERE TO SEND INQUIRIES below. Investigators who lack expertise in stem cell research should seek collaboration with researchers who are familiar with aspects of stem cell research that are relevant to the proposed research. Awardees will be expected to attend one joint meeting every two years in or near Washington, DC, in order to review progress and exchange information. Sufficient funds to support attendance at these meetings should be included in the budget. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Lisa Neuhold, Ph.D. Neuroscience and Genetics Programs Neurosciences and Behavioral Research Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 594-6228 FAX: (301) 594-0673 Email: lneuhold@willco.niaaa.nih.gov Laurie Foudin, Ph.D. Tissue Injury and Fetal Alcohol Research Programs Biomedical Research Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-9812 FAX: (301) 594-0673 Email: Lfoudin@nih.gov o Direct your questions about peer review issues to: Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4375 o Direct your questions about financial or grants management matters to: Ms. Judy Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4704 FAX (301) 443-3891 Email: jsimons@willco.niaaa.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIAAA staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: RFA-AA-02-010 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) FAX: (301) 443-6077 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: Applicants who plan to submit a small grant (R03) application must follow the instructions provided in PAR-99-098, "NIAAA Small Grant Program," http://grants.nih.gov/grants/guide/pa-files/PAR-99-098.html. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $300,000 per year in direct costs must be submitted in a modular grant format. The modular 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 http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three 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) At the time of submission, two additional copies of the application must be sent to: AA-02-010 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAAA. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAAA in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NIAAA National Advisory Council on Alcohol Abuse and Alcoholism. 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 discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your 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, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. o OTHER REVIEW CRITERIA: Additional considerations pertinent to the review of Exploratory/Developmental Grant (R21) and Small Grant (R03) applications include: 1) Pilot/feasibility studies contain little or no preliminary data. Review should focus on whether the rationale for the study is well developed and whether the proposed research is likely to generate data that will lead to a regular research project grant or full-scale clinical trial. Adequate justification for the work may be provided through literature citations, data from other sources, or investigator-generated data. 2) Because the research plan of R03 applications is limited to ten pages, these applications may not have the level of detail or extensive discussion normally found in an R01 application. Review emphasis should be placed on conceptual framework and general approach to the problem, with less emphasis on methodological details. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 15, 2002 Application Receipt Date: May 15, 2002 Peer Review Date: July-August 2002 Council Review: September 2002 Earliest Anticipated Start Date: September 28, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. REQUIRED FEDERAL CITATIONS 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 AMENDMENT "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 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm . 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. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 http://grants.nih.gov/grants/funding/children/children.htm. 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. 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. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.273, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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