PA-03-065: CALCIUM OXALATE STONE DISEASES

Department of Health
and Human Services (HHS)

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CALCIUM OXALATE STONE DISEASES RELEASE DATE: January 30, 2003 PA NUMBER: PA-03-065 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. Accordingly, this funding opportunity expires on the date indicated below. A replacement R21 (PA-06-152) and R01 (PA-06-153) funding opportunity announcements have been issued for the submission date of June 1, 2006 and submission dates thereafter. See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and AIDS-related R03 and R21 Applications. EXPIRATION DATE: March 2, 2006 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov/) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA Urinary tract stone disease constitutes a major health care burden for the United States population, causing significant pain, morbidity, and hospitalization. Recent reports suggest that the incidence of these cases is increasing. The majority of urinary tract stones are composed of calcium oxalate. Genetic studies have identified a small group of individuals with known inherited metabolic disorders who develop recurrent calcium oxalate stones at a very early age. Most of these persons have genetic disorders, called Primary Hyperoxalurias (PHs), which cause defective regulation of oxalate synthesis in the liver, leading to an excessive excretion of oxalate in the urine and the subsequent development of urinary tract stones. The genetic contribution to development of the other, more prevalent, calcium oxalate stone diseases of adults is unknown. Previous studies suggest a familial incidence in a subset of persons who have recurrent urinary tract stone disease. Identification and characterization of families of recurrent stone formers is essential for the identification of unique genetic, environmental and metabolic factors that predispose individuals to recurrent calcium oxalate stone formation. Most importantly, novel and previously unexplored approaches for the effective treatment and prevention of the calcium oxalate urinary tract stone diseases are needed. 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, and to develop new treatments for the disorder. This initiative solicits research as well as pilot and feasibility studies that utilize new and innovative approaches to study the diagnosis, treatment and prevention of these disorders. The Division of Kidney and Urologic and Hematologic Diseases of the NIDDK has identified this initiative as one of a subset of active program announcements (PAs) that are high priority, and warrant a set-aside of NIDDK "Special Emphasis" funds (see http://grants.nih.gov/grants/guide/notice-files/NOT-DK-03-001.html). RESEARCH OBJECTIVES A. Background Although calcium oxalate stone disease is a very common health problem among adults in the United States, it is poorly understood at the basic science level. Previous work has suggested that this disease tends to occur within families but pedigrees have not been well established or studied. There are several rare, heritable causes of nephrolithiasis that result in the onset of oxalate stone disease early in childhood and frequently lead to renal failure. The primary hyperoxalurias (PHs) are known to be due to mutations affecting hepatic enzymes that metabolize glyoxylate. The non- catabolized glyoxylate is oxidized to oxalate and is excreted in excess in the urine. Dent's disease, also known as X-linked recessive nephrolithiasis, is a hereditary condition characterized by hypercalciuria, nephrocalcinosis, and kidney stones. The disease also causes proteinuria, progressive renal failure, and, in some patients, rickets. It is associated with mutations that inactivate the voltage-gated chloride channel ClC-5 In 2002, the NIDDK sponsored two workshops to discuss aspects of hereditary calcium oxalate stone disease. The first, "Hepatocyte-Based Therapies for Oxalosis," was held in June 2002, and focused on the challenges of correcting the hepatic cell enzymatic defect in primary hyperoxaluria that leads to the impairment of the kidney and other organs, but not the liver. The second, "Hereditary Calcium Oxalate Stone Disease Registry Planning Meeting," discussed the need to establish a high-quality registry with detailed data about patients with hereditary calcium oxalate stone diseases. Both meetings highlighted the need for new and innovative research on the molecular etiology (or etiologies) of hereditary calcium oxalate stone disease, as well as for novel and effective treatments and preventive strategies. Similarly, there is a need for research to elucidate the etiology, risk factors, or genetic basis of idiopathic forms of the disease. This announcement focuses on oxalate stone disorders in an attempt to better understand the metabolic, molecular, and genetic defects responsible for the disease and to eventually develop more effective diagnosis, treatment and preventive strategies. B. Objectives and Scope It is the intent of this program announcement to increase novel and productive research focusing on primary hyperoxaluria, Dent's Disease and the recurrent oxalate stone diseases and to encourage both new and experienced investigators from related fields of research to apply their knowledge and skills to this area. Research topics which are included within the scope of this announcement include, but are not limited to: o development of strategies to identify, characterize and investigate family pedigrees with spontaneous calcium oxalate stone disease to study risk factors, genetic defects, environmental factors and other related factors. o identification and characterization of genetic modifier loci that influence the progression of primary hyperoxaluria, Dent's Disease or other heritable recurrent calcium oxalate stone diseases. o development of new or improved animal models for the study of human hereditary and idiopathic calcium oxalate stone diseases, including transgenic animals with conditional mutations o improvement of tools for prenatal or post-natal diagnosis o development of novel strategies to replace, correct, prevent or ameliorate the effects of the genetic defect identified in primary hyperoxaluria or Dent's Disease, including the use of hepatocyte transplantation o studies of methods to correct defective processing, folding or organelle targeting of mutant enzymes o clarification of the etiologic factors for development of oxalate stone disease in patients with bowel disease and identification of improved prevention and therapy options in this patient population o identification of gene expression patterns that are related to the etiology of calcium oxalate nephrolithiasis using microarray, SAGE, or other technologies o elucidation of the molecular events underlying disease progression, including identification of biomarkers that signal susceptibility to development of the disease or specific complications MECHANISM(S) OF SUPPORT This PA will use the NIH R01 (investigator-initiated research project grant) and the R21 (exploratory/developmental research grant) award mechanisms. The R01 mechanism is recommended for applications that propose research for which preliminary data exists. As an applicant you will be solely responsible for planning, directing and executing the proposed project. The R21 award is an exploratory/developmental research grant for support of high-risk pilot and feasibility research designed to develop new ideas sufficiently to allow future submission of a full R01 application. See http://www.niddk.nih.gov/fund/grants_process/revmech.htm for a description of R21 awards. R21 grants awarded through this PA will provide up to $275,000 over two years in direct costs, with a maximum of $175,000 direct costs in any one year, and may not be renewed. The Research Plan section of an R21 application should not exceed 15 pages. Applicants are encouraged to contact program staff for information about choosing the appropriate grant mechanism. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. If the direct costs of your application are greater that $250,000 follow the instructions for non-modular research grant applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS For the duration of their award, investigators must participate in yearly meetings and periodic conference calls organized by the NIH and designed to facilitate the exchange of ideas and findings. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues: o Direct your questions about scientific/research issues to: Rebekah S. Rasooly, Ph.D. Program Director, Genetics and Genomics Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 643 Bethesda, MD 20892-5458 TEL: (301) 594-6007 FAX: (301) 480-3510 Email: rr185i@nih.gov o Direct your questions about financial or grants management matters to: Trude Hilliard Grants Management Specialist National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd., Room 717 Bethesda, MD 20892 Telephone: (301) 451-8859 FAX: (301) 480-4237 Email: th105x@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact Grants Info, Telephone: (301) 710-0267, E-mail: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTION FOR R21 APPLICATIONS: All application instructions outlined in the PHS 398 application kit are to be followed, with the following requirements for R21 applications: 1. R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $175,000 per year. 2. Although preliminary data are not required for an R21 application, they may be included. 3. Sections a-d of the Research Plan of the R21 application may not exceed 15 pages, including tables and figures. 4. R21 appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15-page limit of items a-d of the research plan. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: R01 applications requesting $500,000 or more in direct costs for any one year must get prior approval from NIH before submission, by carrying out the following steps: 1) Contact the IC program staff at least 6 weeks before the submittal deadline; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) DATA SHARING: The adequacy of the proposed plan to share data. Investigators receiving awards will be required to generate a data-sharing plan. This plan will be reviewed for: statements of willingness to share information fully; clarity of included Material Transfer Agreements and Reagent and Animal Transfer Agreements; adequate and clear strategies for sharing results/data, tools, and mice with the research community and/or websites maintained by the NIH. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001(http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants1.nih.gov/grants/funding/women_min/guidelines_amended_10_ 2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.849 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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