RESEARCH STUDIES ON THE HEREDITARY CALCIUM OXALATE STONE DISEASES Release Date: April 27, 2000 PA NUMBER: PA-00-091 National Institute of Diabetes and Digestive and Kidney Diseases THIS PA 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 PA. PURPOSE Urinary tract stone disease constitutes a major health care burden for the United States population. Calcium oxalate is the major constituent of these urinary tract stones. Studies suggest that a subset of persons who have chronic, recurrent urinary tract stone disease have a familial predisposition to the disease. The etiology and the genetic abnormality in these persons are not known. However, there is a group of individuals with known inherited disorders who develop recurrent calcium oxalate stones at a very early age. These persons have a genetic metabolic disorder known as primary hyperoxaluria in which a genetic defect causes excessive excretion of oxalate in the urine. These primary hyperoxaluria disorders have been shown to be due to a defect in the regulation of oxalate synthesis in the liver, resulting in an accumulation of excess oxalate. The purpose of this Program Announcement is to increase investigator interest in research into the genetics and heritability of oxalate regulation and the oxalate stone diseases. The Division of Kidney and Urologic and Hematologic Diseases of the NIDDK has set aside specific funds for pilot and feasibility studies which utilize new and innovative approaches to the study of these disorders. 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. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, 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 PA will use the National Institutes of Health (NIH) pilot and feasibility project grant (R21) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed two years. The total amount of direct costs to be requested for each of the two years may not exceed $100,000 per year. 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 Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm DURATION OF PROGRAM ANNOUNCEMENT This PA will remain active for two years, until October 2002, at which time applications may no longer be submitted in response to this program announcement. RESEARCH OBJECTIVES Although calcium oxalate stone disease is a very common health problem in the United States, there is very little new, innovative research being applied to the understanding of the etiology, risk factors, or genetic basis of this chronic disease. This announcement focuses on the heritable oxalate stone disorders in an attempt to better understand the metabolic and genetic defects responsible for the disease and to eventually develop more effective treatment and preventive strategies. The calcium oxalate stone disease that is most commonly identified in adults is poorly understood from a basic science point of view. It is known that this disease tends to occur within families but pedigrees have not been well established or studied. A rare, heritable cause of nephrolithiasis has been identified and characterized. This disorder results in the onset of oxalate stone disease early in childhood and can frequently lead to renal failure. This disease (primary hyperoxaluria) is due to a defect in the liver peroxisomes of the enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the transamination of glyoxylate to glycine. The non-catalized glyoxylate is oxidized to oxalate and is excreted in excess in the urine. To address these issues and others related to calcium oxalate stone disease, the following are some areas in which it is suggested that applications be submitted: o develop strategies to replace the gene defect in oxalosis and hyperoxaluria, o develop strategies for development of new animal models for the study of the calcium oxalate stone diseases, o develop strategies to assemble and investigate family pedigrees with calcium oxalate stone disease for risk factors, genetic defects, and other related factors. Research applications need not be limited to those areas listed above. All innovative proposals related to the subject are encouraged. Summary It is anticipated that, as a result of the grants funded with this PA, new and innovative approaches will have been developed addressing the genetics and heritability of oxalate regulation and the oxalate stone diseases, and that the data obtained from these pilot studies will be effectively utilized by the investigators to submit competitive investigator-initiated R01 research grant applications. 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 are 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 have been 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 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 may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or 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. Competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types are not relevant applications for submission under the guidelines of this PA. 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 $100,000 per year. 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 $100,000) 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. Indirect costs for subcontracts are included in the total cost budget for the R21 applications submitted in response to this PA. The subcontract costs should not be in modular format but should be rounded to the nearest $1000. 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 program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit the signed, original, single-sided application, including the Checklist, along with five signed photocopies and five collated sets of appendix materials 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) The Center for Scientific Review (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, however, amended applications either investigator initiated or previously submitted in response to the PA may be submitted in response to this RFA, but must meet the guidelines delineated in this announcement. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and 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. 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. o 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? o 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? o 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? o 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)? o 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 Adequacy of plans to include both 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. The reasonableness of the proposed budget and duration to the proposed research will also be reviewed.. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review, o Availability of funds, o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Leroy M. Nyberg, Jr., Ph.D., M.D., Urology Programs DKUHD/NIDDK 6707 Democracy Blvd, rm 627 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301)-480-3510 E-mail: NybergL@extra.niddk.nih.gov or Monica Liebert, Ph.D., Urology Programs DKUHD/NIDDK 6707 Democracy Blvd, rm 623 Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301)-480-3510 E-mail: liebertm@extra.niddk.nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Trude Hilliard Division of Extramural Activities NIDDK 6707 Democracy Blvd, rm 643 Bethesda, MD 20892 Telephone: (301) 594-5452 E-Mail: HilliardT@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93. 93.849. Awards are 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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