MOUSE MODELS OF DIABETIC COMPLICATIONS CONSORTIUM Release Date: October 31, 2000 RFA: DK-01-009 (This RFA has been renewed, see RFA-DK-05-011) National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute National Eye Institute National Institute of Dental and Craniofacial Research Juvenile Diabetes Foundation International Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 28, 2001 PURPOSE The intent of this initiative is to assemble a cross-disciplinary Mouse Models of Diabetic Complications (MMDC) Consortium to develop innovative mouse models that closely mimic the human complications of diabetes. Complications to be examined include diabetic kidney disease, retinopathy, neuropathy, micro- and macrovascular disease, peripheral vascular disease, hypertension, impaired wound healing, diabetic cardiomyopathy, abnormalities of the coagulation system, urinary tract infection, oral diseases, and altered gastrointestinal and bladder function. The first goal of this Consortium is to generate animal models that will be useful for studying disease pathogenesis, prevention, and treatment. The second goal of this Consortium is to test the role of candidate genes or chromosomal regions that emerge from genetic studies of human diabetic complications, particularly diabetic kidney disease and accelerated cardiovascular diseases. Each Unit in the Consortium must contain expertise in mouse genetic engineering, organ- specific phenotyping in the mouse, and at least one diabetic complication. The Consortium will define standards, including gene expression profiling, to validate each diabetic complication model for its similarity to human disease. The Units will utilize innovative mouse genetic engineering techniques to create diabetic mice with altered expression of potential target-organ disease genes. The Units will derive, characterize, validate, and use the models for various aspects of basic, developmental, or translational research, including testing strategies for prevention, early detection, therapy, or diagnostic imaging. Consortium Units will have access to resources, information, technologies, ideas, and expertise that are beyond the scope of any single research team. As mouse models are developed and validated, NIH will provide a mechanism to freely disseminate the mouse models and information related to them to the scientific community. 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, Mouse Models of Diabetic Complications Consortium, is related to the priority areas of Diabetes and Chronic Disabling Conditions and to Chronic Renal Disease. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient"s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but NIH is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "TERMS AND CONDITIONS OF AWARD." This RFA is a one-time solicitation. The total project period for an application submitted in response to this RFA may not exceed five years. The anticipated award date is September 30, 2001. FUNDS AVAILABLE The NIH intends to commit approximately $4,500,000 in FY 2001 to fund up to five to six new Mouse Engineering and Phenotyping Units and one Coordinating and Bioinformatics Unit in response to this RFA. The Juvenile Diabetes Foundation International intends to commit up to $500,000 to this program. Although not participating in the RFA, NIA is interested in co-funding applications that include components relevant to aging. An applicant for a Mouse Engineering and Phenotyping Unit may request a project period of up to five years and budget for direct costs of up to $500,000 per year. Should an applicant plan to include subcontracts to other institutions or organizations, only the direct costs of those subcontracts will be used to tally the direct costs that apply toward the $500,000 direct costs cap, there is no cap on total costs. An applicant for a Coordinating and Bioinformatics Unit may request a project period of up to five years and budget for direct costs of up to $300,000 per year. For further budget information, see the section APPLICATION PROCEDURES. Because the nature and scope of research proposed in response to this RFA may vary, we anticipate that the size of awards will vary also. Although this program is provided for in the financial plans of the NIDDK, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, the NIDDK has not determined whether or how this solicitation will be continued beyond the present RFA. RESEARCH OBJECTIVES Background Recognition, prevention, and treatment of diabetic complications are central problems in both type 1 and type 2 diabetes mellitus. In the United States, diabetes accounts for 42 percent of all new cases of end-stage renal disease, 50 percent of all non-traumatic amputations, and the majority of new blindness in people ages 20-74. More than 60 percent of people with diabetes are affected by neuropathy. Macrovascular complications are a major cause of morbidity and mortality in diabetes, particularly in patients with nephropathy. Major risk factors for macrovascular complications of diabetes are dyslipidemia, hypertension, and cigarette smoking, the same risk factors for cardiovascular disease. Cardiovascular disease is the leading cause of mortality, morbidity, and disability in the United States and is approximately four times higher among diabetic patients compared to non- diabetics. Diabetes also markedly increases the risk of developing oral complications such as severe periodontitis. Because diabetic nephropathy does not occur in over half of patients with diabetes, and because there is significant familial clustering of patients with diabetic nephropathy in the African American and Native American communities, there may be one or more susceptibility genes for diabetic nephropathy. Diabetics are also at risk for developing genetic forms of hyperlipidemia such as familial hypercholesterolemia, suggesting that there may be one or more susceptibility genes for this problem. Genetic technology has advanced so that it is theoretically possible to genetically engineer mice that will develop diabetic complications analogous to the major human complications of diabetes. Such accurate models of human diabetic complications would be especially valuable to analyze the initiation and progression of diabetic complications, to provide the framework for the discovery of genes and cellular parameters that generate susceptibility or provide resistance, to furnish targets for intervention and treatment, and to permit testing of prevention, detection, therapeutic, and imaging strategies in the context of a normal tissue environment. Furthermore, it is now possible to more carefully phenotype both human patients and mouse models using unbiased techniques such as systematic gene expression. Several well-characterized mouse models of diabetes exist, however, these mice models have been used mainly to study the mechanisms for developing diabetes and the metabolic complications. In contrast, the pathogenesis of end-organ damage has received less mechanistic attention. Studies of complications have been largely descriptive--often reporting only histologic changes. Time and funding constraints often do not permit an in-depth, comprehensive analysis and characterization of diabetic complications developed by these mice. Even fewer models are tested for their response to treatment or prevention modalities or their suitability for testing early detection or imaging applications. The genes that confer susceptibility to diabetic nephropathy, accelerated atherosclerosis, or cardiovascular disease are unknown. The possible interrelationships between different complications (for example, neuropathy and macro- or microvascular disease) that interact in diabetic patients have not been systematically studied in animal models. The NIH supports many individual projects that involve the derivation or study of mice that develop diabetes. However, at the present time, the NIH does not support a coordinated, collaborative effort to produce highly accurate mouse models of diabetic complications, particularly for the early design, derivation, characterization, and validation phases of model building. Furthermore, NIH has not ensured that the models and the data relevant to them are readily available to the research community for further investigation or application. Objectives and Scope The intent of this initiative is to assemble projects for a cross-disciplinary, multi-institutional MMDC Consortium whose component teams of investigators will refine or derive accurate mouse models of human diabetes complications. The approaches used for generating, characterizing, and validating the mice for research will reflect the blend of experience and creativity of the Consortium component units and will be originated by these investigators. The Consortium will validate the models for use by the research community for a variety of investigations, including for testing therapeutic, prevention, early detection, or imaging strategies, and assure their availability to the research community. It is anticipated that up to five or six Mouse Engineering and Phenotying Units will be awarded. Each unit will consist of a cross-disciplinary team that may reside, if appropriate, at several institutions. A separate award will support a Coordinating and Bioinformatics Unit. A. Interactions The MMDC Consortium, through its component units, Steering Committee, and other committees will: o Define the parameters by which the diabetic complications will be validated (gene expression profiling, pathology, anatomy and functional phenotype, imaging, etc.), if necessary, the Consortium may acquire new human phenotypic data (for example, by gene profiling), o Define the complications for which appropriate models exist and select those that should be comprehensively characterized and refined, if necessary, o Define the complications for which no acceptable model exists and a model(s) must be designed, derived, and comprehensively characterized, o Define standards for phenotyping, treating, and monitoring diabetic mice (blood sugar, insulin levels, response to glucose load, hyperinsulinemic clamp, etc.), o Define standards for assessing the impact of glycemic control on the development of complications, o Identify technological impediments to designing accurate models, and select strategies to surmount them, o Share technological, methodological, and phenotype information both between component Units and with the broader research community, o Share engineered mice between Units so mice can be phenotyped for a variety of diabetic complications, o Decide when a model is sufficiently characterized and validated so that the model itself, and all available accompanying data, can be distributed to the research community for individual investigator-initiated projects. At each step, input will be sought from experts both within the MMDC Consortium, within other NIH-sponsored consortia [for example, D-GAP (RFA DK- 97-007), Familial Investigation of Nephropathy of Diabetes (RFA DK-99-005), and Mouse Metabolic Phenotyping Centers for Models of Diabetes and its Complications (RFA DK-00-014)], and from the broader research community. The NIH will establish the required distribution systems to disseminate the mouse models to the research community. During the course of the funding period, technologies will improve and the rate of progress and scope of research under the cooperative agreement may change. Principal Investigators, in consultation with NIH program staff, will be expected to make necessary adjustments to accommodate the changing research environment, to remain focused on appropriate goals, to maintain excellent coordination with the other projects funded under this RFA, and to incorporate new technological advances. B. Mouse Engineering and Phenotyping Units Each Unit will be a self-assembled group of investigators from one or more institutions who contribute to the MMDC Consortium a unique blend of complementary research experience. An applicant team will incorporate an appropriate mix of expertise needed to achieve the Unit’s goals and to contribute substantially to achieving the overall MMDC Consortium goals. Units will be expected to focus on either one or a small number of diabetic complications. Units do not need expertise in all areas of diabetes complications. Each team must contain expertise in mouse genetic engineering, organ-specific phenotyping in the mouse, and at least one diabetic complication. Additional areas of expertise may include, but are not limited to: mouse genetics, phenotypic, genotypic, and genomic analyses of resulting strains, mouse or human pathology, mouse models of human diabetic complications, small animal imaging technologies, animal husbandry, mechanism, therapy, prevention, early detection, or diagnostic imaging research, and the clinical properties of human diabetic complications that inform the design of therapy, prevention, and early detection strategies. The approaches used to generate, characterize, and validate mouse models will reflect the blend of experience and creativity of the component investigators. The following example is intended only to provide broad direction and should be considered illustrative, but not restrictive. An individual application might: 1. Propose standards for validating a particular diabetic complication. If insufficient information is available, the Unit may propose to obtain more human anatomic, pathologic, or gene expression information from existing databases. 2. Review the literature for existing models and pathogenic mechanisms. 3. Propose to cross diabetic mice with transgenic mice containing organ- specific (or complication-specific) susceptibility loci. The proposal should discuss the clinical relevance of both the diabetic mouse model and the diabetic complication. The genetic manipulation might include standard transgenic knock-in or knock-out approaches, cell-specific or temporal- specific approaches, or both. Alternatively, the diabetic manipulation might be temporally specific. 4. Propose methods to extensively characterize the mice at various times for both diabetes and the particular diabetic complication using physiological, pathological, imaging, and gene-profiling methods. Mice would be treated or partially treated with insulin to prevent malnutrition, wasting, and volume depletion and to assess the role of glycemic control on the complication. 5. Compare the mouse phenotype with data from previous human studies. 6. Use the models to find susceptibility loci and to test therapeutic, prevention, early detection, and imaging strategies. Participating NIH Institutes have briefly outlined broad areas of biomedical interest related to the goals of this RFA. NIDDK: Produce and validate mouse models of diabetic kidney disease, urinary tract infections, altered gastrointestinal and bladder function, and the diabetic foot. Susceptibility loci might include, for example: fibrosis- promoting genes (TGF-beta), cell-cycle control (p21), COX-2, renin/angiotensin system, or glomerular podocyte genes (ureteroglobin, nephrin). NHLBI: Produce and validate models of macro- and micro-vessel accelerated atherosclerosis, peripheral vascular disease, inflammation, hypertension, impaired wound healing, diabetic cardiomyopathy, and abnormalities of the coagulation system. Examples of susceptibility loci might include genes regulating lipoproteins, lipoprotein receptors and associated enzymes, chemotactic substances (e.g. MCP-1), adhesion molecules (e.g. VCAM), hemodynamic forces-affected genes, genes affecting coagulation (PAI-1), platelet glycoprotein receptors (IIB/IIIa), alpha2/beta1 integrins, and the renin/angiotensin system. NEI: Produce and validate mouse models of diabetic retinopathy. NIDCR: Produce and validate mouse models of oral complications of diabetes, such as periodontitis, oral mucosal infections, salivary gland dysfunctions, and oral neuropathies. Applicants must provide methods to maintain Unit records, establish, standardize, document, and distribute protocols, and provide for quality control and budgetary oversight. Each Mouse Engineering and Phenotyping Unit will establish a database to store, organize, analyze, or visualize data generated by individual Units to facilitate dissemination of information and data-sharing within the Consortium. Applicants must also provide methods to establish priorities among mouse models and to oversee the daily operation of Units. It is anticipated that these proposals will be quite speculative and innovative, and applications may lack preliminary data on specific effects of a genetic manipulation on the diabetic complication or feasibility of a particular approach. However, applications should include sufficient information to indicate that the applicant team has sufficient expertise with proposed techniques and that the proposed projects are feasible. C. Data Sharing 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 (http://grants.nih.gov/grants/policy/nihgps, Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html)]. Biomaterials (engineered mice) and other research resources that can be patented (e.g., phenotypic screens and genetic and phenotypic data for all mouse strains) produced in projects funded by this RFA are expected to be made available and distributed to the broader scientific community. The NIH is interested in ensuring that research resources developed through this RFA become readily available to the research community for further research, development, and application, with the expectation that sharing will lead to products and knowledge to benefit the public. For this reason, NIH is concerned that patents on mouse strains, phenotypic screens, and phenotypic and genetic data for all mouse strains and other research resources might have a chilling effect on the future development of products and information that may improve the public health. At the same time, NIH recognizes the rights of grantees to elect and retain title to subject inventions developed with Federal funding under the provisions of the Bayh-Dole Act. All applications are expected to include the following (see the section SPECIAL INSTRUCTIONS ): o Proposed sharing plans to insure that mice, phenotypic screens, and genetic and phenotypic data for all mouse strains are widely available to the scientific community. o A proposed plan addressing if, or how, the PI and grantee institution will exercise their intellectual property rights regarding patentable research resources, such as engineered mice, phenotypic screens, and phenotypic and genetic data for all mouse strains produced in projects funded under this RFA. Applicants are encouraged to discuss proposals for addressing these requirements with their institutional offices of technology transfer. D. Coordinating and Bioinformatics Unit The Coordinating and Bioinformatics Unit will establish and maintain an Internet-based mechanism for rapid data and document transmission and electronic communication among participants in the MMDC Consortium and between the MMDC Consortium and the NIH. The Unit will also establish and maintain a centralized and comprehensive Internet-based mouse database that will compile important information about mouse strains developed and studied by the MMDC. These databases and web sites will serve the needs of all Units established by this initiative and will be an important interface between the MMDC Consortium and the larger research community. Applicants should address data sharing, confidentiality, and security considerations. The Coordinating and Bioinformatics Unit will also provide travel and meeting support for the Steering Committee and other committees of the MMDC Consortium (see the section SPECIAL INSTRUCTIONS ). E. Steering and Other Committees The Principal Investigator and co-PI must be willing to be part of a Steering Committee that will meet twice each year together with NIH program staff to encourage exchange of information among investigators who participate in this program. The Steering Committee may form other committees (for example, model validation, model phenotyping, technology) that will meet once or twice a year either in person or by telephone conference calls. A major goal of these meetings is to facilitate progress by providing a forum for sharing skills, ideas, technology, data, and biological reagents. At the meetings, participants will also discuss quality assurance, bioinformatics, coordination, and training. If voting is necessary for an action item, NIH Program Scientists will share one vote. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator(s) and to the institutional official at the time of award. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient"s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities to carry out the studies will be shared by awardees and NIH Program Scientists. 1. Awardee Rights and Responsibilities o The PI will have primary authority and responsibility to define objectives and approaches and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award. o The PI will assume responsibility and accountability to the applicant organization officials and to the NIH Institutes for the performance and proper conduct of the research supported by the project in accordance with the terms and conditions of the award. o The PI and another senior investigator will serve as voting members of the Steering Committee, will attend the Planning Meeting and two Steering Committee meetings in the first year, and two Steering Committee meetings a year in subsequent years. o The PI will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the Steering Committee and subcommittees. o The PI will be responsible for close coordination and cooperation with the other components of the MMDC Consortium and with the NIH staff. o Awardees will retain custody of, and have primary rights to, the data developed under these awards, subject to Government rights of access consistent with current HHS and NIH policies. Investigators conducting biomedical research frequently develop unique research resources. The policy of the PHS is to make available to the public the results and accomplishments of the activities that it funds. All awardees must adhere to PHS policy for the distribution of unique research resources produced with PHS funding that was published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 25, No. 23, July 12, 1996), and is available at the following Internet address: http://grants.nih.gov/grants/guide/notice-files/not96-184.html. o NIH reserves the right to require the transfer of appropriate mouse stocks, related reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party, in order to preserve the mouse models and data about them and/or to continue the research. Third parties supported under these awards must be informed of this right. o Effective conduct of the MMDC Consortium goals will require considerable electronic communication of data and other information among the MMDC Consortium components and between the components and the NIH. Consortium members will be required to demonstrate that they have the ability to transfer data accurately and effectively. o The Coordinating and Bioinformatics Unit will coordinate the logistics of all MMDC Consortium Steering Committee meetings, other MMDC Consortium committee meetings, and workshops and provide an internet-based mechanism for electronic communication among the MMDC Consortium components and the NIH. 2. NIH Staff Responsibilities NIH Program Scientists from each participating NIH institute will have substantial scientific-programmatic involvement during conduct of this activity, through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below. The dominant role and prime responsibility for the project as a whole resides with the awardees, although specific tasks and activities in carrying out the studies will be shared by awardees and the NIH. The NIH will form an NIH MMDC Consortium External Coordinating Committee, comprised of the NIH Program Scientists and other NIH extramural staff with relevant scientific expertise or who manage research grant programs that relate scientifically to the goals of the MMDC, and outside advisors picked by the NIH. The External Coordinating Committee will meet regularly to review the progress of the MMDC Consortium and to advise the NIH Program Staff of scientific developments and opportunities that may enhance the achievement of the MMDC Consortium goals. o NIH Program Scientists from the participating institutes will be members of the Steering Committee and, as determined by that committee, its subcommittees. o NIH Program Scientists will coordinate and facilitate the MMDC Consortium programs, attend and participate as voting members in all meetings of the MMDC Consortium Steering Committee, and provide liaison between the Steering Committee, the MMDC Consortium, and participating institutes. o NIH Program Scientists will help the Steering Committee develop and draft operating policies and policies addressing recurring situations that require coordinated action. o NIH Program Scientists will review the scientific progress of the individual Units, review Units for compliance with operating policies developed by the Steering Committee, and may recommend to the funding institutes to withhold support, suspend, or terminate an award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. 3. Collaborative Responsibilities Steering Committee The NIH Program Scientists and awardees comprising the MMDC Consortium will be responsible for forming a Steering Committee as defined below. An arbitration system, as detailed below, will be available to resolve disagreements among members of the Steering Committee. The Steering Committee will be the main governing board of the MMDC Consortium. It will develop collaborative protocols, set priorities for model derivation, define parameters for model validation, identify technological impediments to success and strategies to overcome them, and decide when models should be made available to the research community for individual investigator-initiated projects. o The Steering Committee will be composed of the PI and a co-PI or other senior investigator from each Mouse Engineering and Phenotyping Unit and the Coordinating and Bioinformatics Unit, and NIH Program Scientists. The two investigators from each Unit will share one vote. The NIH Program Scientists will share one vote. The Steering Committee will select a chairperson who will be someone other than an NIH staff member. o The Steering Committee may, as it deems necessary, invite additional, non-voting scientific advisors to meetings at which research priorities and opportunities are discussed. The NIH reserves the right to augment the scientific or consumer expertise of the MMDC Consortium when necessary. o There will be two Steering Committee meetings annually, one in July in the Washington, DC, area and the other at a time and site agreed upon by the Steering Committee and the NIH. o The first meeting of the MMDC Consortium will be a Planning Meeting in the Washington, DC, area soon after grants are awarded. At the Planning Meeting, the Steering Committee will be formed and select a chairperson from among the members who represent the awardees. At the Planning Meeting, the Steering Committee may: (a) draft a charter to detail policies and procedures, a process for monitoring compliance with the policies and procedures, and a process for recommending that the NIH Program Administrators act on evidence of non-compliance of any Consortium component with Steering Committee policies, (b) agree upon the terms of the charter, (c) discuss the models and approaches that were proposed in the project applications and any relevant new information, and set initial priorities for the models to be derived and for new technologies to be developed, (d) discuss and set initial genotypic and phenotypic parameters required to characterize the models and to define their comparability to human diabetic complications, (e) discuss and set initial standards for validating the models for further biological studies and such uses as testing prevention or early detection strategies, or therapies, or diagnostic imaging technologies. At the first meeting of the Steering Committee following the Planning Meeting, an Internet-based electronic communications mechanism will be discussed and will be implemented by the Coordinating and Bioinformatics Unit. o At their first meeting each year, the Steering Committee will formulate plans for any workshops or symposia to be held. o At the second and subsequent meetings, the Steering Committee will refine the MMDC Consortium’s scientific objectives and characterization and validation strategies as necessary, consistent with progress in the MMDC Consortium components and other laboratories, and with the goals of identifying available models with sufficient promise for further testing, or defining those human diabetic complications for which models must be created de novo. o At any time during the MMDC Consortium project, the Steering Committee may examine the characterization and validation data for models derived by the MMDC Consortium components and decide when a model is sufficiently validated that it may be distributed to the research community for further investigations or applications. The NIH will provide the means to disseminate the mice. o The Steering Committee will plan workshops to which non-MMDC Consortium participants will also be invited to (a) enable the MMDC Consortium to explore scientific or technologic innovation that occurs during the course of the project, (b) inform the research community of the progress made toward derivation or refinement of models or their characterization and validated uses, and (c) inform the research community of any technological advances related to design and derivation of mouse models. The NIH Program Scientists, the MMDC External Coordinating Committee, and other NIH staff will provide the Steering Committee with advice on participants for the workshops and symposia. The Coordinating and Bioinformatics Unit will manage the logistics for these meetings. o The Steering Committee may establish subcommittees, as it deems appropriate, NIH Program Scientists and other NIH staff who are Steering Committee members will serve on subcommittees as they deem appropriate. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the U01 award) between awardees and the NIH may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with the NIH Program Scientists not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NIH Program Scientists, and, the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at: http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit by February 28, 2001, a Letter of Intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NIDDK staff to estimate the potential review workload and to plan the review. The Letter of Intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Room 653 MSC 5452 Bethesda, MD 20892-5452 Bethesda, MD 20817 (for express/courier service) Tel: (301) 594-8885 Fax: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these awards, with the modified format that is described below. These forms are available at most institutional offices of sponsored research, from GrantsInfo, Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, Suite 6095, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 2a of the face page of the application form and the YES box must be marked. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in PDF format. 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 also be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Room 653 MSC 5452 Bethesda, MD 20892-5452 Bethesda, MD 20817 (for express/courier service) Tel: (301) 594-8885 Applications must be received by March 28, 2001. 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 announcement 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 an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. SPECIAL INSTRUCTIONS Applicants may apply for a Mouse Engineering and Phenotyping Unit, a Coordinating and Bioinformatics Unit, or both. If an applicant applies for both, separate applications must be submitted. 1. General Application Format Instructions The form PHS 398 should be modified as follows. Biosketches and "Other Support" pages should be included for all personnel. The number of pages allowed for the "Research Plan" is increased from 25 to 40 pages for the Mouse Engineering and Phenotyping Units, but remains at 25 pages for the Coordinating and Bioinformatics Unit. Budget pages, budget justifications, material transfer agreements, and letters from collaborators and consultants and their biosketches are not included in this limit. 2. Applications for Mouse Engineering and Phenotyping Units Applicants for the Mouse Engineering and Phenotyping Units should divide the "Research Plan" into the sections indicated below. Part 1. Infrastructure. In this part of the "Research Plan," applicants should detail the specialized or unique facilities, fundamental infrastructure, research expertise, and core resources and services that are available to support the planned mouse model derivation, characterization, and validation. If facilities at more than one institution are required, applicants should thoroughly describe them and obtain appropriate assurances. Methods for mouse, data, and information flow and sharing within the Unit should be described. Applicants should discuss their barrier facilities, requirements for importing non-SPF animals, and where the phenotyping will be performed (behind a barrier or in a regular laboratory). The location of any imaging equipment should be specified (i.e., is the imaging equipment in a barrier facility?). The roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be well documented. Applicants must also provide methods for establishing priorities among mouse models. An internal advisory board consisting of the Principal and co-Investigators and other important personnel should oversee the daily operation of the Unit. Applicants should describe how the Unit will fit into, augment, and be supported by the parent institution and plan for designating an alternate or replacement Principal Investigator should it become necessary. Part 2. Model Derivation. In this part of the "Research Plan," applicants should discuss the clinical relevance of both the diabetic mouse model and the diabetic complication. Applicants should discuss their rationale for the design and derivation of a new mouse model or models, or for altering and improving an existing model or models, based on their experience with mouse models of human disease and their knowledge of basic, translational, and clinical diabetes research. Applicants should describe the extent to which they plan to characterize any models they derive or refine, the methods that they will use to characterize the models, the rationale for choices of methods, and how generally applicable the methods are, or will be, for all mouse diabetes and diabetes complication models. In this part as well, applicants are expected to identify the standards they will apply to validate a model or models, the rationale for the choices, how generally applicable the validation standards are, or will be, for all mouse diabetes or diabetes complication models, and, the purpose(s) for which they anticipate their models may be used. Applicants should describe their barrier facility, requirements to bring non-SPF animals into their institution, and the location of the phenotyping Unit relative to the barrier. The roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be thoroughly documented. Part 3. Technology. In this part of the "Research Plan," applicants should define the technologic approaches they will use, or any technology that they propose to develop, to achieve the goals of model derivation or refinement, characterization, and validation. The roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be thoroughly documented. Part 4. Interactions with Other MMDC Consortium Components and the Research Community. In this part of the "Research Plan," applicants must include specific plans for responding to the "Terms and Conditions of Award" section. Applicants should state their willingness to collaborate and share data freely with the other MMDC Consortium components and the wider research community. Applicants must include a data sharing plan, a mouse sharing plan, and copies of all Material Transfer Agreements and Mouse Transfer Agreements used by all institutions involved in the application. Applicants are encouraged to use the NIH Simple Letter of Agreement to transfer materials, available at http://www.ott.nih.gov/policy/rt_guide_final.html#guide. Applicants should discuss their willingness to serve on the Steering Committee and other Consortium committees and should state their willingness to follow the common protocols that will be developed by the Steering Committee, particularly those that relate to setting priorities for model development and the standards for characterization and validation. Applicants must state their willingness to plan and attend workshops and symposia. Applicants should describe how their unique blend of experience can contribute to the collective efforts of the MMDC Consortium. Applicants should also describe how they will comply with the involvement of NIH Program Scientists and fulfill the responsibilities of Consortium components to work together cooperatively. Applicants should describe their experience with, and capability for, Internet-based communication and ideas for facilitating electronic communication and other interactions among the MMDC Consortium components, NIH, and the general research community. The scientific review group will evaluate the adequacy of the proposed plan for sharing and data access. Comments on the plan and any concerns will be presented in an administrative note in the summary statement. The adequacy of the plan will be considered by NIH program staff and will be important in determining whether the grant shall be awarded. The sharing plan(s) as approved, after negotiation with the applicant when necessary, will be a condition of the award. Evaluation of non-competing continuation applications will include assessment of the effectiveness of research resource release. Applicants are reminded that the grantee institution is required to disclose each subject invention to NIH within two months after the inventor discloses it in writing to grantee institutional personnel responsible for patent matters. The awarding Institute reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications on mice identified through phenotypic screens, phenotypic screens, and phenotypic and genotypic data for all mouse strains or other patentable subject matter are adversely affecting the goals of this RFA. 3. Applications for the Coordinating and Bioinformatics Unit Applicants for the Coordinating and Bioinformatics Unit should discuss Infrastructure, Technology, and Interactions, as described above. Part 2 above should be omitted. This narrative should include, for example: Part 1. Infrastructure. Applicants should discuss the administrative structure of the coordinating Unit and plans for providing administrative support for up to five meetings a year. Part 3. Technology. Applicants should describe the Internet-based mechanism for rapid electronic communication among participants and the NIH, the structure of the centralized and comprehensive database, and web sites for communication within the MMDC consortium and with the research community. Applicants should describe issues of data validity, security, and confidentiality. Part 4. Interactions with other MMDC Components and the Research Community. Applicants should discuss data sharing and willingness to participate in common activities, committees, and workshops as outlined in Part 4 above. Applicants must include a data sharing plan and copies of the Material Transfer Agreements used by all institutions in the proposal. 4. Budget Instructions Applicants who have additional funds to support ( leverage ) the application should indicate the source of funds (institutional, R01, P01, P30, etc.) that permit them to accomplish the project goals. Subcontract budgets should be a separate page, and the subcontract indirect costs should be calculated and listed in the usual place as part of the direct costs of the budget. However, only direct costs associated with each subcontract will count toward the direct costs cap of $500,000 on the budget for the first year. Specific budget issues related to cooperative agreements must also be addressed as follows. o Applicants must budget for travel and per diem expenses for participation in the MMDC Consortium Steering Committee, subcommittees, workshops, and symposia. Applicants should budget for seven trips to the Bethesda, MD, area each year. o Applicants for the Coordinating and Bioinformatics Unit should include travel support for 15 additional outside consultants to attend Steering and other committees meetings and workshops in the Bethesda, MD, area each year. REVIEW CONSIDERATIONS General Considerations All applications will be judged on the basis of the scientific merit of the proposed project and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of the RFA. Although the technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a study. Other factors considered to be important for review include demonstrated expertise in mouse genetic engineering and phenotyping as applied to the design and derivation of mouse models of human disease, a multi-disciplinary team of collaborators, substantial interactions among collaborating researchers, demonstration of appropriate facilities and resources, willingness to share data and reagents freely. Supplemental information of up to three pages will be allowed if received by May 1, 2001. Send materials to Chief, Review Branch, at the address above. Review Method Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete applications will be returned to the applicant without further consideration. 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 NIDDK in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council, the National Heart, Lung, and Blood Advisory Council, the National Eye Advisory Council, and the National Dental and Craniofacial Research Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the cooperative study and their specific protocols, and they are expected to address issues identified under TERMS AND CONDITIONS OF AWARD and SPECIAL INSTRUCTIONS sections of the RFA. The peer review group will assess the scientific merit of the applications and related factors using the following criteria: 1. Innovation. Does the project employ novel concepts, approaches or method? Is the project original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Will the approaches advance the field of mouse or other model development? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Can these approaches be used to derive mouse models of diabetic complications in addition to those proposed? Are the parameters chosen to characterize the model(s) sufficient and appropriate? Are these parameters generally applicable to all mouse diabetic complication models? Are the standards chosen to validate the model(s) for its relevance to a human diabetic complication or for testing therapy, prevention, early detection, or imaging appropriate and adequate? 3. Significance. Do the model or models proposed for derivation/ characterization/validation address an important need for the diabetic complication research community? What is the immediacy of the research opportunity? Over the project period, is there potential for the group to develop models other than those specified in the application? 4. Investigators. Are the principal investigator and his/her collaborators appropriately trained and well suited to carry out this work? To what extent do these investigators have the necessary complementary skills? Have collaborations been established or consultants identified to provide the appropriate depth and breadth of scientific expertise required for the project? Will this team of investigators contribute unique skills to the overall Consortium? 5. Environment. Are the facilities for mouse maintenance and experimentation appropriate to support the endeavor? 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 and incorporate the best use of collaborative arrangements? Is there evidence of institutional support? If advanced imaging techniques are proposed, is the instrument located behind an animal barrier? Additional Considerations 6. Interactions. Are there adequate plans for effective interaction and coordination among Consortium components and the NIH? Are the proposed plans to share data and mice adequate? Do the investigators state their willingness to collaborate extensively and share information fully? Are the Material Transfer Agreements and Mouse Transfer Agreements straightforward? Do the investigators state their willingness to abide by the priorities and policies agreed upon by the Steering Committee? Have the applicants proposed sound strategies for communication among themselves, with the other MMDC components, and with the NIH? 7. Budget. Assess the appropriateness of the proposed budget and duration in relation to the proposed research. Does the budget for fundamental infrastructure, model development, characterization and validation, and technology development indicate that the applicants understand the requirements of managing this sort of model-building enterprise? 8. Coordinating and Bioinformatics Unit. Does the Unit employ novel concepts, approaches or methods? Are the principal investigator and collaborators appropriately trained and well suited to provide support for multiple investigative teams and to design and implement internet-based Web sites and databases? Are the computer facilities (hardware, software, and personnel) sufficient to support the endeavor? Are there adequate plans for providing meeting support, Internet-based communication, databases, and web sites for use by the MMDC Consortium? Have the applicants addressed data sharing policies, confidentiality issues, and security considerations? Are there adequate plans for open access to these databases and web sites by the general research community? AWARD CRITERIA The intent of this RFA is to enable the NIDDK to assemble a Consortium of highly qualified Units of investigators whose complementary scientific skills and expertise will enable them to achieve the goal of deriving validated mouse models that are analogous to human diabetic complications. The NIDDK will choose Units for the Consortium that will collectively provide the most creative approaches to mouse model design, and have a range of research focus, experience, technology, and resources to ensure that a range of models of diabetic complications are rapidly derived and validated. Applications recommended by the NIH Advisory Councils will be considered for award based upon (a) scientific and technical merit as determined by peer review, (b) the importance of the proposed models for research in diabetic complications, (c) the degree of originality and innovation in model design, (d) the creativity of the approaches and technologies for model derivation, characterization, and validation, (e) the likelihood for substantial contribution by the applicants to a successful collaborative MMDC, (f) the evidence for willingness to work cooperatively, (g) the quality and availability of animal research infrastructure and resources, (h) program balance, including, in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood, and (i) the availability of funds. Schedule Public Information Meeting: December 2000 Letter of Intent Receipt Date: February 28, 2001 Application Receipt Date: March 28, 2001 Peer Review Date: June-August 2001 Council Review: September 2001 Earliest Anticipated Start Date: September 30, 2001 INQUIRIES A public information meeting will be held in December 2000 in Bethesda, Maryland. The date and time of this meeting, answers to frequently asked questions, and other updates about this RFA will be posted on the NIDDK Web site (or http://www.niddk.nih.gov/fund/crfo/highlights.htm) as they are developed. Applicants are highly encouraged to visit this Web site regularly in the course of preparing applications. Potential applicants are encouraged to subscribe to the MMDC Discussion List at list.nih.gov/archives/mmdc-l.html . These sites will contain the most current information available. Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues that are not addressed at the website to: Robert A. Star, M.D. Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 31 Center Drive, Room 9A35 Bethesda, MD 20892-2560 Tel: (301) 594-7717 Fax: (301) 496-2830 E-mail: Robert_Star@nih.gov Momtaz Wassef, Ph.D. Atherosclerosis Research Group Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge 2, Room 10193Bethesda, MD 20892-7956 Tel: (301) 435-0550 Fax:(301) 480-2858 E-mail: Wassefm@NIH.gov Nancy L. Nadon, Ph.D. Head, Office of Biological Resources and Resource Development National Institute on Aging 7201 Wisconsin Ave./ GW 2C231 Bethesda, MD 20892 Tel: (301) 496-6402 Fax: (301) 402-0010 E-mail: nadonn@exmur.nia.nih.gov Dennis F. Mangan, Ph.D. Infectious Diseases and Immunity Branch Division of Extramural Research National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-32F Bethesda, MD 20892-6402 Tel: (301) 594-2421 Fax: (301) 480-8318 E-mail: Dennis.Mangan@nih.gov Direct inquiries regarding fiscal matters to: Teresa Farris Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Room 630 MSC 5456 Bethesda, MD 20892-5456 Tel: (301) 594-7682 Fax: (301) 480-3504 E-mail: FarrisT@extra.niddk.nih.gov Ms. Jane R. Davis Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge 2, Room 7174 Bethesda, MD 20892-7926 Tel: (301) 435-0149? Fax: (301) 480-3310 E-mail: Davisj@NIH.Gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121, 93.837, 93.847, 93.848, and 93.849. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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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