THE LIFE CYCLE OF THE ADIPOCYTE RELEASE DATE: October 10, 2002 RFA: DK-03-002 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( National Institute on Aging (NIA) ( LETTER OF INTENT RECEIPT DATE: February 14, 2003 APPLICATION RECEIPT DATE: March 14, 2003 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 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Aging (NIA) invite investigator-initiated Research Projects (R01 and R21) to study the life cycle of adipocytes. This initiative encourages investigators to develop the necessary biological procedures and reagents for characterization of adipocyte progenitor cells at multiple stages of determination and commitment into the adipocyte lineage, for use in identifying fat cell commitment factors, and to use in the study of adipose tissue turnover and remodeling. The goal of this initiative is to increase our understanding of the life cycle of human adipocytes and to catalyze the development of novel treatments for metabolic diseases including type 2 diabetes, obesity, familial lipodystrophy, and acquired lipodystrophy associated with HIV infection and treatment. RESEARCH OBJECTIVES Background The adipocyte is a key cell in the development of many metabolic diseases including diabetes, obesity, and both familial and acquired lipodystrophy. Previous work supported by NIDDK and NIA have demonstrated important roles for hormones, receptors and/or transcription factors, such as peroxisome proliferator-activated receptor gamma?(PPAR-gamma) and CCAAT box enhancer binding protein alpha?(C/EBP-alpha), in fat cell differentiation. Continued dissection of the pathways involved in differentiation of preadipocytes into adipocytes while important, is NOT the focus of this initiative. Rather, the current initiative is designed to encourage studies of the factors and pathways involved in the commitment of progenitor cells into the adipocyte lineage; to increase our understanding of the cues signaling turnover and remodeling of adult adipocytes from various fat depots; to determine how fat tissues are maintained during adult life; to investigate how adipocytes are affected by age and environmental factors; and to understand more about how the life cycle of adipocytes is regulated in health and disease. Recent advancements in our understanding of stem cell and progenitor cell biology, and the development of methods for whole genome and proteome analyses allow new approaches to be applied to the study of the adipocyte life cycle. Moreover, the ready accessibility of both peripheral and visceral adipose tissues to biopsy makes fat tissue a reasonable target for animal and human studies. The Human Genome Project and similar work in other species have made it possible to address in new ways the important biological problems of how different tissues and organs develop from small founder populations of stem cells, how organs reach optimal size, are maintained throughout adult life, and sometimes regenerate, and the effects of age and disease on this capacity. There is emerging evidence that progenitor cells of different tissues may share some common basic molecular mechanisms that allow them to self-renew in the presence of appropriate environmental cues. The elucidation of these mechanisms offers the promise of providing a complete understanding of the factors that maintain normal tissues in health, and the promise for novel approaches to the study of pathogenesis and treatment of human diseases. In addition, the Congressionally-established Diabetes Research Working Group (DRWG) report "Conquering Diabetes, A Strategic Plan for the 21st Century" and an international workshop, entitled "Lipoatropic Diabetes and Other Syndromes of Lipodystrophy", emphasized the importance of obtaining a greater understanding of the life cycle of insulin responsive tissues (e.g. liver, skeletal muscle, and fat) in healthy individuals, the cross-talk among these tissues, and elucidating how the life cycle of these tissues is altered in metabolic diseases such as diabetes and obesity. Furthermore, with the widespread use of highly active antiretroviral therapy (HAART) for the treatment of HIV disease, patients are now living longer. Although the overall health of HIV-infected individuals is improving, concerns are now arising that HAART therapies may be associated with adverse metabolic effects, such as hyperlipidemia, insulin resistance, and changes in body composition. Loss of subcutaneous fat in the buttocks, face and/or extremities, either alone or in combination with abnormal fat accumulation in other locations, has been widely reported in patients with HIV infection over the past few years. The mechanisms underlying these various HIV associated lipodystrophies, and their connection with antiretroviral therapies presently remains unclear. Scope of Research The NIDDK and NIA intend to support multidisciplinary investigator-initiated projects (R01s) that explore fundamental aspects of the life cycle of the adipocyte, as well as Exploratory/Development Research projects (R21s). Investigators applying to this RFA are encouraged to use genome-wide studies (genomics and proteomics), advanced lineage tracing techniques, analytic methods, and state-of-the-art cell biological approaches to study mouse and human fat cell commitment/determination, adipocyte trans-differentiation and remodeling, adult adipocyte turnover, and investigate how these processes are altered by metabolic diseases such as diabetes, obesity and lipodystrophy. Areas of research opportunities include, but are not restricted to the following: o Develop advanced tools and technologies to study the mechanism(s) used by mice and humans to "signal" adult adipocytes to turnover or trans- differentiate o Develop advanced tools and technologies to study the mechanism(s) used by mice and humans to "signal" progenitor cells to commit to the adipocyte lineage o Measure and compare the turnover rates of fat cells from various depots, and investigate if and how these turnover rates are impacted by the development of diabetes, obesity, and lipodystrophy or by treatment with insulin sensitizing drugs or anti-retroviral therapies (e.g. specific HIV protease inhibitors and nucleoside reverse transcriptase inhibitors) o Define and/or develop specific biomarkers, such as high-specificity antibodies or reporter gene constructs, for detection, classification, and isolation of adipocyte progenitor cells at multiple stages of development or in distinct fat depots. This might include the development of reliable and convenient clonogenic assays for cell populations in developing and adult tissues so that these cells can be purified and characterized o Profile mRNA or protein expression in the relevant cell populations or particular fat depots during aging or under different metabolic conditions or drug treatments o Use in silico methods to identify novel genes and transcript splice forms specifically expressed in the targeted cell populations or specific fat depots o Produce and sequence full-length cDNA libraries and truncation libraries, in which cDNAs are inserted downstream of a consensus translation initiation sequence and an oligopeptide tag in an effort to generate dominant negative protein fragments that can be expressed and studied in cells o Develop custom clone sets for use in microarrays or other high-throughput gene expression assays; use of arrays to characterize changes in gene expression patterns in the target cell population during development, trans- differentiation, tissue remodeling or disease progression o Develop and apply single-cell gene expression methodologies to various adipocyte populations MECHANISMS OF SUPPORT This RFA will use the NIH investigator-initiated Research Project Grant (R01) and the Exploratory/Development Research Grant (R21) award mechanism(s). As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators; 2) allow exploration of possible innovative new directions for established investigators; and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $150,000 direct costs per year and are limited to two years. These R21 grants will not be renewable; continuation of projects developed under this program will be through the regular research grant (R01) program. This RFA uses just-in-time concepts. It also uses the modular 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 format. Otherwise follow the instructions for non- modular research grant applications. FUNDS AVAILABLE The participating IC(s) intend to commit approximately $2 million dollars in FY 2003 to fund 3 to 6 new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $450,000 per year for more complex, multidisciplinary R01 applications, and $150,000 per year in direct costs for up to 2 years for R21 applications. 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 IC(s) 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(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 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 Restricted availability of unique research resources, upon which further studies are dependent, can impede the advancement of research and delivery of medical care. Sharing biomaterials, data, and software in a timely manner has been an essential element in the rapid progress that has been made in the genetic analyses of mammalian genomes. NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication [NIH Grants Policy Statement (; Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999( Biomaterials (constructs, cell lines, etc.) and other research resources that can be patented (e.g., software tools, expression data) that are produced in projects funded by this RFA are to be made available and distributed to the broader scientific community. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA 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: Carol Renfrew Haft, Ph.D. Adipocyte Program Director Division of Diabetes, Endocrinology and Metabolism National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 605 Bethesda, MD 20892-5460 Telephone: (301) 594-7689 FAX: (301) 480-3503 E-mail: David B. Finkelstein, Ph.D. Biology of Aging Program National Institutes on Aging 7201 Wisconsin Avenue, Suite 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 E-mail: o Direct your questions about financial or grants management matters to: Mary K. Rosenberg Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 722 Bethesda, MD 20892-5456 Telephone: (301) 594-8891 FAX: (301) 480-3504 E-mail: Linda Whipp Grants and Contracts Management Office National Institutes on Aging 7201 Wisconsin Avenue, Suite 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 E-mail: 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 IC 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: Carol Renfrew Haft, Ph.D. Adipocyte Program Director Division of Diabetes, Endocrinology and Metabolism National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 605 Bethesda, MD 20892-5460 Telephone: (301) 594-7689 FAX: (301) 480-3503 E-mail: 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 in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SPECIFIC INSTRUCTIONS FOR R21 APPLICATIONS All application instructions outlined in the PHS 398 application kit are to be followed, with the following requirements for R21 applications: 1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $150,000 per year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15 page limit of items a-d of the research plan SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 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 includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at 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: 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 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 NIDDK and NIA. 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 CSR 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 National Diabetes and Digestive and Kidney Diseases Advisory Council. 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? Does your study provide an important resource and how will the resource(s) impact the 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? For R21 applications, is there evidence of feasibility? (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 DATA SHARING: The adequacy of the proposed plan to share data. Do investigators state their willingness to submit data to a public database in a timely fashion or make the information available to the community at large in another way? Do the investigators agree to share reagents such as knock- out mice, cell populations, plasmids and antibodies? The plans proposed for sharing and data release will be reviewed for adequacy by reviewers as well as NIDDK staff prior to award and will be considered as a criterion for award. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. Funds to defray the costs of submitting data and distribution of reagents may be included in the application. Such requests must be adequately justified. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 14, 2003 Application Receipt Date: March 14, 2003 Peer Review Date: July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 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 MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: 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 (; 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. 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 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 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. 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.866 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 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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