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PROTEOMICS IN DIABETES AND OTHER ENDOCRINE AND METABOLIC DISEASES RELEASE DATE: January 7, 2003 PA NUMBER: PA-03-052 EXPIRATION DATE: After 02/01/2006, unless reissued. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) National Cancer Institute (NCI) (http://www.nci.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Information about a Workshop on Proteomics o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA This program announcement is part of a larger NIDDK and NCI proteome initiative and seeks to promote the use of proteomic technologies for studying diabetes and its complications, and other endocrine and metabolic diseases. The development and improvement of innovative proteomic technologies is also encouraged through their application to relevant biological questions related to diabetes, endocrinology and metabolic diseases. RESEARCH OBJECTIVES Background High throughput DNA sequencing has changed biomedical research. The complete sequence of the genome for 100 organisms and the nearly complete sequence of many others, including the human, are giving a new vision to the study of biological systems. It is, however, apparent that knowledge of the genome alone is not sufficient for a complete understanding of complex biological processes. While the genome is the same in different cell types within an organism and does not change with time, the proteome varies with time and among different cell types. The gene function is usually fulfilled through its protein whereas its potential is indicated by the genome. In view of recent large-scale data showing that often there is a poor correlation between mRNA quantities and protein quantities, we cannot limit gene expression studies to the RNA level but must also investigate biological problems at the protein level. Despite the significant limitations of using mRNA arrays for studying gene expression, relatively few investigators have used proteomic approaches. Moreover, post-translational modifications, regulation of protein function by proteolysis, and composition of macromolecular complexes or organelles can only be determined at the protein level, further emphasizing the importance of studying the proteome. Proteomic approaches have been successfully used for studying complex biological problems and for the identification of disease markers. Recent developments in proteomics indicate that the technologies available are already sufficiently advanced to approach many biological questions relevant to the NIDDK mandate. Some of these technologies include: two-dimensional gel electrophoresis for profiling complex mixtures coupled to mass spectrometry or other methods for protein identification; isotopically labeled reagents for the comparison of two different biological states (e.g. disease versus control) using mass spectrometry; protein or antibody arrays; yeast two- hybrid systems, phage display or immunoprecipitation coupled to mass spectrometry for studying protein-protein interactions; characterization of macromolecular complexes using antibodies, DNA, RNA, or other molecules as bait followed by identification by mass spectrometry; and computational methods for structure/function prediction. None of the above technologies is capable of analyzing the whole proteome at once. However, the study of a subset of the proteome is feasible, and could be applied to a specific biological system and/or disease of interest. There is also a need to further improve the present technologies and develop novel approaches for studying the proteome that are more sensitive and more comprehensive. These technology developments would be of particular interest when accomplished through projects directed at understanding or solving problems related to organs and/or diseases of interest to the NIDDK Examples of projects that the NIDDK and NCI is soliciting through this PA include but are not limited to: o Identification of surrogate markers looking at the plasma/serum proteome at different stages of development of diabetes, its complications or other endocrine or metabolic diseases. o Use of proteomic approaches to study the signal transduction network of the insulin receptor and/or other cell surface receptors (e.g. G-protein coupled receptors (GPCR), Ser/Thr kinase receptors, growth factor receptors, and cytokine receptors) relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Characterization of the proteome or a subset of the proteome of animal and cell models relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Use of proteomic approaches for studying carbohydrate, lipid and protein metabolism, hormonal control of metabolism and its alteration in diabetes and other endocrine or metabolic diseases. o Identification of novel signaling molecules and pathways involved in cell development, differentiation, communication, function and destruction, as applied to diabetes, endocrinology, and metabolic diseases. o Use of proteomic approaches for studying the regulation, synthesis, secretion, and action of hormones and cytokines relevant to diabetes, its complications, and endocrinology and metabolic diseases. o Use of proteomic approaches for the characterization of macromolecular complexes relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Use of proteomic approaches to study nuclear receptors (e.g. steroid and thyroid hormone and orphan nuclear receptors) and their action, including the roles of receptors and/or nuclear accessory proteins, including coactivators, corepressors, and chromatin remodeling protein complexes. o Use of proteomics to characterize the signal transduction networks of one or more specific receptor system(s) to determine mechanisms underlying specificity of response integration of signaling systems, and coupling hormone signaling to changes in gene expression. o Use of proteomic approaches for identifying surface markers for monitoring pancreatic beta cell differentiation, development, function, and/or mass. o Development and/or use of computational proteomics tools to analyze and/or annotate the genome as it might apply to information relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Development and/or use of bioinformatics tools to study the proteome as it might apply to information relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Identification of novel drug targets or novel therapeutic agents using proteomic approaches that might be relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Characterization of the proteome or a subset of the proteome for toxicology studies of drugs that might be relevant to diabetes, its complications, or other endocrine or metabolic diseases. o Characterization of the effect on the proteome or a subset of the proteome of drugs/agents that are currently used to treat or prevent diabetes, its complications, or other endocrine or metabolic diseases. The above examples are not meant to be comprehensive or to restrict ideas to these particular concerns. However, they do represent some of the projects that would be relevant to the NIDDK and NCI mission. MECHANISM(S) OF SUPPORT This PA will use the NIH R01 and R21 award mechanisms. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. For the R21 there is a limit of 2 years at $100,000/year in requested support. This PA 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 $250,000 or less, use the modular format. Otherwise follow the standard instructions in the PHS 398 form. FUNDS AVAILABLE The NIDDK recently announced that it will decrease the use of one-time solicitations, (e.g. the request for application (RFA) mechanism) and substitute use of special emphasis funding for selected program announcements (PA) to stimulate research in areas of particular importance. Applications responsive to these Special Emphasis PAs will receive automatic consideration for funding beyond the regular grant payline. The NIDDK is strongly committed to the use of proteomic technologies to advance research in diabetes, endocrinology and metabolic diseases, and has selected this PA to be a Special Emphasis PA. Further information about NIDDK Special Emphasis PAs can be found at http://www.niddk.nih.gov/fund/fund.htm. Funding will also be dependent on the receipt of applications of high scientific merit and on the availability of funds for this purpose. This PA will remain active through the February 1, 2006 receipt date, after which applications submitted within the scientific scope of this PA will compete without the special emphasis benefit. 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 WORKSHOP ON PROTEOMICS This PA is one component of a multi-faceted initiative to foster application of proteomic technologies to diabetes, its complications, and other endocrine and metabolic diseases. Another component of the proteome initiative is the workshop Proteomics in Diabetes that will occur in Bethesda on April 23-25, 2003 (http://www.niddk.nih.gov/fund/other/proteomics/index.htm). Importantly this workshop will provide a venue to bring together investigators with expertise in proteomics and those interested in applying this technology to a problem related to diabetes, endocrinology and metabolic diseases. Important goals of the workshop will be exchange of information as well as fostering new research collaborations among participants. All prospective applicants are invited to attend. NIDDK and NCI staff will be available to answer any questions about the solicitation. In addition, the workshop will facilitate identification of potential research partners and initiation of collaborative efforts, which may be important for development of a successful application. The NIDDK anticipates participants in this workshop will be drawn from multiple disciplines spanning the technology and biology fields. 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 encouraged to apply. 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: Salvatore Sechi, Ph.D. Director, Proteomic Program Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd. Rm. 611 Bethesda, MD 20892-5460 Telephone: 301-594-8814 FAX: 301-480-2688 Email: ss24q@nih.gov Mukesh Verma, Ph.D. Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., Rm. EPN 3144 Rockville, MD 20852-7362 Telephone: 301-496-3893 FAX: 301-402-8990 Email: mv66j@nih.gov o Direct your questions about financial or grants management matters relevant to: Ms. Denise Payne Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Rm.733 Bethesda, MD 20892-5460 Telephone: 301-594-8845 FAX: 301-480-3504 Email: dp43b@nih.gov Mr. Brian E. Martin Grants Management Specialist National Cancer Institute 6120 Executive Blvd., Rm. EPS 243 Bethesda, MD 20892-7148 Telephone: 301-846-7148 FAX: 301-846-5720 Email: bm215c@nih.gov 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. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm, and include February 1, June 1, and October 1. These application deadlines are also indicated in the PHS 398 application kit. 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 $100,000 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 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. 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; 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 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 or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. 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 application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council or the National Cancer Advisory 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 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. 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? 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? 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? 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)? 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: 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. INCLUSION: The adequacy of plans to include subjects from 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) 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 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: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). 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 PA 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. 93.847 (NIDDK) and 93.393 (NCI) 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 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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