INSULIN SIGNALING AND RECEPTOR CROSS-TALK RELEASE DATE: July 28, 2003 PA NUMBER: PA-03-156 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. Replacement R01 (PA-06-175) and R21 (PA-06-176) funding opportunity announcements have 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: March 2, 2006 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( National Institute on Aging (NIA) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847, 93.866 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 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 The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute on Aging (NIA) invite investigator-initiated research grant applications that will investigate crosstalk in insulin responses at molecular, cellular, and physiological levels. The purpose of this initiative is to stimulate novel and innovative research into the fundamental mechanism(s) of action of the insulin receptor in target tissues in the context of other cellular receptors and signaling pathways, and to broaden our understanding of how insulin signals act to regulate coordinated responses between and among insulin responsive tissues. Of particular interest is how such signaling interactions may affect the development and/or progression of diabetes and its complications. This program announcement replaces PAS 99-112. RESEARCH OBJECTIVES Background Diabetes currently affects an estimated 16 million Americans, and is the sixth leading cause of disease-related death in the US. With the diagnosis of approximately 800,000 new cases each year, the health and economic burden of diabetes continues to escalate. Given the magnitude of the problem and its enormous impact on patient health and welfare, there is an urgent need to define the factors contributing to diabetes onset and severity, and to identify new potential therapeutic targets. A defining feature of Diabetes mellitus is the inappropriate regulation of serum glucose levels. Both type 1 and type 2 diabetes are associated with insulin deficiency, with type 2 diabetes further complicated by cellular resistance to insulin action. Obesity, a condition that itself is rising in prevalence, is a major risk factor for development of both insulin resistance and type 2 diabetes. While the precise relationship between obesity, type 2 diabetes, and insulin resistance remains under investigation, emerging data suggests that changes in insulin receptor regulated signaling pathways are involved. The insulin receptor plays a dominant role in mediating insulin's effects. However, insulin target tissues also respond to hormones, growth factors and cytokines that have the potential to modify insulin responses. Receptors for many of these soluble factors initiate signals that may overlap or modulate insulin-stimulated biochemical pathways, and in this way impact the quality or quantity of the insulin response. For example, members of the growth factor, cytokine, and G-protein coupled receptor families are all expressed in various combinations in insulin responsive tissues. Stimulation of these receptors and the signaling pathways they regulate has the potential to alter the strength, duration, or character of the insulin response. Thus, signals initiated via the insulin receptor must be interpreted by cells in the context of multiple biochemical signals that arise in the complex microenvironment found in insulin-responsive tissues. Intracellular interactions between insulin dependent biochemical events and signals transduced via other signaling pathways, or "crosstalk", may occur at multiple levels, including at the level of receptor function, substrate availability, signal flow through downstream pathways, and/or integrated control of gene expression. Cross-talk also occurs between insulin-responsive tissues, with recent evidence suggesting that insulin signals elicited in one target tissue impact responses in other organs and at distant sites. While significant progress has been made in defining the biochemistry of the insulin-response pathway, in documenting insulin-regulated changes in gene expression and in elucidating the crosstalk that occurs between insulin responsive organs, important scientific gaps remain to be explored. For example, our understanding of how a cell's complex biochemical history may modify subsequent responses to insulin, and of how multiple environmental cues regulate insulin action within and between target tissues in vivo, remains rudimentary. Information generated via these and related studies of signaling crosstalk within and between insulin-responsive tissues has the potential to provide important insights into the mechanisms that underlie diabetes pathophysiology, and may have important implications for the design of new therapeutics to treat diabetes and its complications. Objectives and Scope This Program Announcement solicits investigator-initiated research projects that will define the mechanistic basis of crosstalk between the insulin receptor signaling pathway and other signaling pathways, with the goal of defining how insulin action is influenced by the complex microenvironment found in insulin responsive tissues. Appropriate topics for investigation under this PA would include, but are not limited to: o determining the specificity of signaling through the insulin receptor, including delineation of metabolic versus mitogenic responses; o signaling through receptors for other soluble factors found in insulin target tissues, including growth factors and cytokines, and potential modifying effects of these soluble factors on insulin action, diabetes pathophysiology and its complications; o signals initiated by adhesion molecules such as integrins in insulin- responsive tissues, including receptors involved in regulating intercellular communication and interactions with the extracellular matrix, and the impact of these signals on insulin responses in vitro and in vivo. o interactions between and among insulin responsive tissues, including factors mediating organ-specific crosstalk in insulin-driven responses; o age-related changes in insulin sensitivity at the level of the insulin receptor and its activating ligand(s), insulin receptor signaling pathway, cross-talk with other intracellular signaling pathways, and/or altered gene and protein expression profiles in insulin-responsive tissues; o factors regulating cell surface expression of functional insulin receptors and other cell surface receptors in diabetes and its complications; o interactions between and among transcription factors that mediate the effects of insulin on gene expression: cross-talk with transcription factors responding to other signaling pathways; o signaling cross-talk between the insulin receptor and nuclear receptors, including effects on development and/or progression of diabetes and its complications; o identification of factors involved in cell signaling that may cause resistance to insulin action in insulin-sensitive cells (e.g. muscle, adipose) and novel approaches to overcome or bypass such resistance; o genomic, proteomic, and other state-of-the-art biochemical approaches to identify novel factors associated with insulin action in target tissues, including putative targets for therapeutic intervention; o structural biology of cell surface receptors and signal relay molecules that transduce or modify insulin actions, including enzymes, protein scaffolds, and higher-order complexes capable of integrating signals generated by receptor cross-talk in insulin-responsive cells; o the mechanism of action of non-peptide receptor analogs and their potential efficacy as therapeutic agents. Information generated via these and related studies of signaling crosstalk in insulin-responsive tissues has the potential to provide important insights into the mechanistic basis of diabetes pathophysiology. These insights may in turn have important implications for the design and implementation of new therapeutics to treat diabetes and its complications MECHANISM(S) OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) and the Exploratory/Development Research Grant (R21) award mechanisms. As an applicant, you will be solely responsible for planning, direction, and executing the proposed project. This PA uses just-in-time concepts. It also uses the modular budgeting format. (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at The R01 award represents an investigator-initiated research grant designed to support a discrete, specified research project performed by a principal investigator. R01 applications may request up to $250,000 per year in direct costs for a maximum of five years. R21 (Exploratory/Developmental) grants (see The R21 mechanism is intended to encourage new exploratory/developmental research projects by providing support for the early stages of their development. Awards are made to demonstrate feasibility of a subsequent project and to obtain preliminary data testing innovative ideas. Therefore, these grants are not renewable. Continuation of projects developed under this program will be through the regular research project grant mechanism (for example, R01). These grants are not intended to support or supplement ongoing funded research of an established investigator, or to serve as an alternative mechanism of support for projects not receiving funding as competitive continuation applications. The NIH Grants Policy statement applies to these awards. An R21 application should have a research plan that does not exceed 15 pages. A two-year project period is the maximum period of support. You may request a project period of up to two years with a combined budget for direct costs 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. Little or no preliminary data are required. Up to five relevant published articles may be included as Appendix material, if desired. Exploratory/developmental grant support is for new projects only; competing continuation applications will not be accepted. Two revisions of a previously reviewed exploratory/developmental grant application may be submitted as defined in NIH Policy at 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 o Faith-based or community-based 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 Plan for Dissemination of Data and Biomaterials Sharing of biomaterials, data, and software in a timely manner has been an essential element in the rapid progress that has been made in the genetic analysis of human diseases. 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 ( All applicants who respond to this PA must propose plans for sharing data and biomaterials generated through the grant. Applicants should explain how funds for the storage and distribution of data and biomaterials will be obtained, and may request such funds in the budget of the application. It is expected that the information to be shared will include clinical, diagnostic, and pedigree structure information. Biomaterials to be shared should include patient DNA and cell lines. When possible, data and biomaterials should be placed in databases or repositories that will permit their efficient distribution to investigators throughout the scientific community. Rapid sharing of data and biomaterials is strongly encouraged. 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. NIH staff will consider the adequacy of the plan and determine 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: Kristin Abraham, Ph.D. Cell Signaling Program Director Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 607 Bethesda, MD 20892-5460 Telephone: (301) 451-8048 FAX: (301) 480-3503 E-mail: Frank Bellino, PhD Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: o Direct your questions about financial or grants management matters to: Randi Freundlich, R.D. Grants Management Specialist Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 723 Bethesda, MD 20892-5456 Telephone: (301) 594-8825 FAX: (301) 480-3504 E-mail: Jeff Ball Grants and Contracts Management Office National Institute on Aging Gateway Building, Room 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: 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: 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 GRANT APPLICATIONS: All investigator- initiated R21 applications 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 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 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. An appropriate scientific review group 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 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 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 discuss the following aspects of the 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 the application's overall score, weighting them as appropriate for each application. 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. SPECIAL CONSIDERATION FOR THE R21 APPLICATION: The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools or technologies that have the potential to significantly advance our knowledge or the status of health- related research. Because the research plan is limited to 15 pages, an exploratory/developmental grant application need not have background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. 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. 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 "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 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). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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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