FOODBORNE ILLNESSES, GASTROINTESTINAL AND RENAL COMPLICATIONS Release Date: November 30, 1999 RFA: DK-00-005 National Institute of Diabetes and Digestive and Kidney Diseases American Digestive Health Foundation Letter of Intent Receipt Date: February 23, 2000 Application Receipt Date: March 23, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases in partnership with the American Digestive Health Foundation invites experienced and new investigators to submit research grant applications to pursue basic and clinical investigations to further the understanding of foodborne illnesses and especially the gastrointestinal disease and renal injury of E. coli 015:H7-induced hemolytic uremic syndrome. The proposed studies should foster and extend the understanding of the pathogenesis and pathophysiology of foodborne disease, including: the mechanisms by which bacterial toxins induce endothelial cell damage and renal injury, and the mechanisms by which bacterial, viral, and fungal organisms and products cause gastrointestinal and extra-gastrointestinal injury. Other areas which have potential for further investigation include genetic factors that determine gastrointestinal as well systemic diseases expression, markers of genetic susceptibility to complications of foodborne disease, the natural history and epidemiology of the enteric infection as well as the extra- intestinal manifestations, the risk factors for the acquisition, transmission and expression of foodborne disease particularly in children and the elderly, human markers of genetic susceptibility to complications of foodborne disease, the development of experimental models of foodborne diseases, and the identification and testing of interventions that might lead to improved management of gastrointestinal disease as well as extra-gastrointestinal complications. Of prime importance is the development of new diagnostic and therapeutic techniques that would lead to early medical intervention and prevention of complications of foodborne illnesses. The intent of this solicitation is to intensify investigator- initiated research, to attract new investigators to the field, and to increase interdisciplinary research. The ultimate aim is to encourage and facilitate research studies in this area where progress already attained offers new opportunities to increase the pace with which knowledge is accrued. In recognition of the importance of these research questions, The American Digestive Health Foundation, a cooperative effort of the American Gastroenterological Association, the American Society of the Gastrointestinal Endoscopy, and the American Association for the Study of Liver Diseases, are co-sponsoring this solicitation and will be providing partial funding through NIH for direct costs of the portfolio of grants that receive support under this initiative. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), FoodBorne Illness, Gastrointestinal and Renal Complications is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, and laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and the R21 mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The R21 provides limited funds (maximum of $100,000 direct costs per year) for short-term (up to two years) research projects. R21 grants are nonrenewable, but continuation of the projects developed under these grants can be supported by the investigator initiated research project grant (R01) mechanism. Specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm Modular Grant applications will request direct costs in $25,000 modules. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions. FUNDS AVAILABLE For FY 2000, $2.1 million dollars will be committed to fund applications submitted in response to this RFA. It is anticipated that 10 to 12 awards will be made. An applicant for an R01 award may request a project period of up to 5 years and a budget for direct costs of up to $200,000 (8 modules) per year, including Facilities and Administration (F & A) costs on consortium (subcontract) arrangements. An applicant for an R21 award may request a project period of up to two years and a budget for direct costs of up to $100,000 (4 modules) per year, including F & A costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of the awards will also vary. Although the financial plans of the NIDDK, and the American Digestive Health Foundation (ADHF) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. RESEARCH OBJECTIVES Background While the United States food supply is among the safest in the world, every year there are millions of American stricken by foodborne illnesses. The Centers for Disease Control and Prevention (CDC) estimate that there are up to 80 million foodborne-related illnesses per year. Foodborne illnesses tend disproportionately to affect the very young and the elderly. Threats to the food and water supply are numerous and varied, and include Escherichia coli (E. coli 0157:H7) in meat and juices, Salmonella in eggs or vegetables, Cyclospora on fruit, Cryptosporidium in drinking water, and hepatitis A virus in frozen berries. In January 1997, a Presidential Initiative was announced requesting an increase in the 1998 federal budget to fund a nationwide early warning system for foodborne illnesses, increased seafood safety inspection, and expanded food safety research and training education. The President directed the Departments of Agriculture and Health and Human Services (DHHS) and the Environment Protection Agency to identify specific steps to improve the safety of the food supply. This RFA is designed to support basic and clinical research on the biology, human genetics, and pathogenesis of the disease process, natural history and epidemiology of foodborne illnesses. Because induction of foodborne illnesses is one mechanism through which bioterrorism may take place, an improved awareness of the pathobiology of foodborne illnesses and the underlying mechanisms should lead to more effective diagnostic approaches to these illnesses and provide better means of prevention and treatment. Relevant topics of research include, but are not limited to the following: Objectives: o Identification of mechanisms by which E. coli and other pathogen- related toxins induce epithelial (cells of the gastrointestinal tract) and endothelial cell damage and mechanisms leading either to recovery or permanent damage within the kidneys and (or) the gastrointestinal tract. o Development of experimental in-vivo models for studies of the pathogenesis of the disease and particularly to test therapies as these are identified, also the development of animal models of disease, such as genetically engineered mice that express modified levels of glycolipid receptors on endothelial cells. o Studies of human genetic susceptibility, i.e., host factors that regulate the survival of the pathogens in the gastrointestinal tract or the kidneys, and other host factors that determine the biological response to the initiating events, the severity of tissue injury, and the eventual disease outcome. Included should be the role of the investigation of the remaining genes in the pathway of the verotoxin receptor. o Studies of the sources, role, and mechanisms by which cytokines and other various inflammatory mediators elicit signals and/or traffic between the renal and gastrointestinal vascular endothelium with consequent long-term effects on kidney function and histopathology. o Discerning the role of activated inflammatory cells in presenting endothelial injury, as well as the specific role of reactive nitrogen or oxygen molecules by activated monocytes and polymorphonuclear leukocytes. o Studies of markers of gastrointestinal and renal injury, as well as markers of disease severity are encouraged. o Enhancing the understanding of the role of the direct toxin damage to endothelial cells vs. toxin-induced cytokine damage. o Studies of the mechanisms by which verotoxins cause changes/alterations in endothelial cell tight junctions with increased permeability and altered expression of cell surface adhesion molecules, leading to morphologic alterations and endothelial cell detachment characteristic of HUS, also, elucidation of the mechanisms leading to either endothelial cell recovery or permanent damage. o Epidemiologic studies to characterize environmental as well as human genetic factors in familial clustering of foodborne illnesses and their extra-gastrointestinal manifestations. o Development of intervention strategies to prevent the transit of the verotoxin, including the design and testing of soluble toxin receptor analogs in appropriate systems. o Identification of host-based and clinical strategies to prevent complications of E.coli 0157:H7-related illnesses during the initial critical interval between the occurrence of hemorrhagic colitis and the development of HUS. Investigators are not limited to the above examples of the research focus and are encouraged to propose other approaches that are appropriate to the investigator initiated grant mechanism and to the requirements of this RFA. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18,1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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 March 23, 2000. 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. LETTER OF INTENT Prospective applicants are asked to submit, by February 23, 2000, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the 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 a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities NIDDK, NIH Building 45 Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $200,000 per year for R01s or $100,000 for R21s. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $200,000 for R01s and $100,000 for R21s) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. 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 your application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label is 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 time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK Natcher Building, Room 6AS-37F 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless Applicants are notified by the Scientific Review Administrator. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIDDK CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications 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 NIDDK National Diabetes and Digestive and Kidney Diseases Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. SCHEDULE Letter of Intent Receipt Date: February 23, 2000 Application Receipt Date: March 23, 2000 Peer Review Date: June-July, 2000 NIDDK Advisory Council Review: September, 2000 Anticipated Award Date: September 30, 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific and technical merit (as determined by peer review o programmatic priorities o program balance o availability of funds INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Frank A. Hamilton, M.D., MPH Chief, Digestive Diseases Program Branch DDDN/NIDDK Natcher, Bldg. Room 6AN12B 45 Center Drive MSC 6600 Bethesda, MD 20892 6600 Telephone: (301) 594-8877 FAX: (301) 480-8300 Email: hamiltonf@extra.niddk.nih.gov Gladys Hirschman, M.D Director, Chronic Renal Diseases and Pediatric Nephrology Program, DKUHD NIDDK Natcher Bldg. Room 6AS-13 45 Center Drive, MSC 6600 Bethesda, Md. 20892-6600 Telephone (301) 594-7717 FAX: (301) 480-3510 e-mail: gladys_hirschman@NIH.Gov Direct inquiries regarding fiscal matters to: George Tucker, MBA Deputy Chief, Grants Management Branch Division of Extramural Activities NIDDK/Natcher Bldg. 45/6AS49E 45 Center Drive Bethesda, MD 20892 Telephone: 301 594-8853 FAX: 301 480-3504 Email: tuckerg@extra.niddk.nih.gov Aretina Perry-Jones Division of Extramural Activities NIDDK, NIH 45 Center Drive Room 6AN-38B Bethesda, MD 20892-6600 Telephone: (301)594-8862 FAX: (301) 480-3504 Email: perrya@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.848, 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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 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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