NEW APPROACHES TO IMPROVE THE VIABILITY AND FUNCTION OF TRANSFUSED PLATELETS NIH Guide, Volume 26, Number 35, October 17, 1997 RFA: HL-97-016 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: November 28,1997 Application Receipt Date: January 22, 1998 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING RESPONSES TO THIS RFA. PURPOSE The Transfusion Medicine Scientific Research Group, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute (NHLBI), announces the availability of a Request for Applications (RFA) on the above subject. The purpose of this initiative is to encourage the conduct of research on the alterations produced in blood platelets during collection/ processing and storage, on the development of detection techniques for monitoring viability and function of platelets after collection/processing and during storage, and on the prevention of defects responsible for loss of function. The recent availability of sophisticated tools and analytical techniques to study the platelet surface components, evidence that platelet storage and viability can probably be improved, and need to make maximum use of blood products, make it possible and timely to pursue such questions in an important area of hematologic research and national health need. Thus, the intent of this solicitation is to: (a) encourage established investigators with available tools to devote resources to this area; (b) attract new scientific expertise such as cell biology, biochemistry, molecular biology, into studies of platelet viability and function; and (c) promote inter-disciplinary collaborative research in helping to solve a fundamental question in hematology; i.e., what biologic events result in loss of platelet viability and/or function after collection/processing and during storage and how can these events be prevented. The ultimate goal will be to define the conditions which will provide better hemostatic function as a result of platelet transfusions to thrombocytopenic patients. 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 RFA, New Approaches to Improve the Viability and Function of Transfused Platelets, is related to the priority areas of heart diseases and stroke, and cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state or local governments, and eligible agencies of the federal government. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Minority individuals and women are encouraged to apply. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Newly independent investigators who may wish to consult with a program representative (see "INQUIRIES" section) are encouraged to apply. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 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. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of seven modules ($175,000 direct costs) per year may be requested. Any necessary escalation must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Applicants, who will plan and execute their own research programs, are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to 4 years of support may be requested. At the end of the official award period, renewal applications may be submitted for peer review and competition for support through the regular grant program of the NHLBI. It is anticipated that support for the present program will begin September 1998. Administrative adjustments in project period or amount of support may be required at the time of the award. Since a variety of approaches would represent valid responses to this announcement, it is anticipated that there will be a range of costs among individual grants awarded. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded in connection with this RFA. FUNDS AVAILABLE It is anticipated that for fiscal year 1998, $1,200,000 total costs will be available for the first year of support for this initiative. The award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that approximately four to six new grants will be awarded under this program. Applicants may request up to four years of support. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and Administrative costs will be awarded based on the negotiated rates. If collaborative arrangements involve subcontracts with other institutions, Ms. Jane R. Davis of the NHLBI Grants Operations Branch (telephone: (301) 435-0166) should be consulted regarding procedures to be followed. RESEARCH OBJECTIVES BACKGROUND Platelets are enucleated cell fragments produced from megakaryocytes and are essential to prevent or stop microvascular bleeding. Platelet transfusions to treat hemorrhagic thrombocytopenia have increased dramatically from 410,000 units in 1971 to 7,258,000 units in 1989. Recently, a marked increase has been noted in transfusions of single donor apheresis platelets. Between 1992 and 1994, single donor apheresis platelet transfusions increased from 3,642,000 to 4,284,000 unit equivalents (expressed as platelets harvested from one unit of donated blood), an increase of 23.6%. In 1994, transfusions of single donor platelets actually exceeded transfusions of platelet concentrates for the first time. Platelets demonstrate a progressive loss in viability during storage. At one large regional blood center, 156 consecutive platelet transfusion-refractory patients were examined to determine the mechanism of their platelet refractoriness. Of these, 108 (69%) had no evidence of platelet-reactive antibodies. Only 3 of these non-alloimmune platelet-refractory patients did not show improved responses when they were given "fresh" platelets that were stored for less than 30 hours. Responses to fresh vs. stored platelets were as much as a 4-fold increase in posttransfusion platelet increment, and a 2-fold increase in platelet survival. Thus, the frequency with which patients may develop refractoriness to stored platelets and the magnitude of the differences in patients' responses to fresh and stored platelets all suggest that improvements in the quality of stored platelets would result in major improvements in the management of thrombocytopenic patients, accompanied by cost savings At least part of this loss in platelet viability may represent activation during collection/processing and storage resulting in platelets that are prematurely removed from circulation. To begin to improve or extend the shelf-life of platelets, it is essential to understand and define better the alterations that take place in these cells. Therefore, it is important to conduct basic research on the cellular and molecular changes leading to the loss of platelet viability and/or function in vitro. Previous studies have demonstrated that stored platelets gradually lose their ability to aggregate or secrete cytoplasmic granular materials upon activation with physiologic stimulants. This loss could, in part, be due to a general decay in the metabolic activities of the cell. Some investigators have reported alterations in the contractile proteins, e.g., myosin or actin-binding platelet proteins. Others have observed changes in specific surface glycoproteins of stored platelets. However, these studies have been sporadic, and the results reported by one investigator have not always been reproduced in another laboratory. There are accumulating data to suggest that it may now be possible to identify an artificial medium that will meet the metabolic needs of platelets during storage much better than the anticoagulated plasma with red cell preserving capabilities that is currently used. In some studies, inhibitors that prevent platelet activation during storage have been added to the medium, resulting in further improvements in platelet viability. These results indicate that there are newer approaches for storing platelets that need to be developed, tested, and refined with the expectation that the quality of stored platelets will be significantly enhanced. The clinical relevance for understanding the biological changes during platelet storage is well-recognized. The demand for platelets to support patients: 1) with dilutional thrombocytopenia due to massive blood transfusions; 2) being treated with aggressive cancer and marrow transplant chemotherapy regimens causing bone marrow suppression; or 3) with other specific thrombocytopenic episodes, is steadily increasing. In addition to the already- identified need for platelet therapy, the platelet demands are expected to increase as more hematopoietic abnormalities occur in AIDS patients such as bone marrow dysplasia, anemia, thrombocytopenia, and leukopenia. This special grant program is for the support of research addressing fundamental questions concerning: 1) how normal platelet function is maintained; 2) what alterations in platelet biology, physiology, or biochemistry develop during collection and storage; 3) how these changes during storage can be prevented ; and 4) does prevention of these storage changes result in improved posttransfusion viability and/or storage for long periods of time in the cold, and 5) can systems be developed that will detect non- viable platelets in storage and prevent their transfusion. The emphasis of this program is clearly on the cellular and molecular properties of platelets. Extensive clinical trials are not deemed appropriate for this solicitation although investigators are encouraged to propose some extension of basic studies into a clinical setting to correlate in vitro changes with in vivo events. Particular encouragement is offered to investigators possessing modern tools who are well-trained in relevant techniques and are currently pursuing other research interests. It is hoped that inter-disciplinary and collaborative approaches may be developed which will complement the efforts of workers in the field. Collaborative research among disciplines such as hematology, biochemistry, cell biology, pharmacology, and molecular biology may be necessary to achieve some of the goals of this study. Examples of topics that might be appropriate for this program are: o Storage-related changes in platelet internal structures including the cytoskeleton and contractile proteins. o Role of proteases, especially calcium-activated proteases, in causing structural alterations leading to loss of platelet function. o Correlations of in vitro changes with alterations in platelet viability or function in vivo. o Development of conditions for storing platelets in the cold without inducing the "platelet lesion". o Development of conditions which might circumvent storage-induced changes and improve platelet viability and function. o Development of procedures and parameters to more accurately assess the viability and/or function of stored platelets. o Effect of additives on the changes produced on the platelet surface due to collection/processing and storage. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program. Travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland, should be included in the modules. Applicants should also include a statement in the applications indicating their willingness to participate in such meetings. 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 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 of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by November 28, 1997, 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. Such letters are requested only for the purpose of providing an indication of the number and scope of applications to be received; therefore, their receipt is usually not acknowledged. A letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for the application. The letter of intent is to be sent to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: james_scheirer@nih.gov APPLICATION PROCEDURES Application Receipt Date: January 22, 1998 Applications are to be submitted on the research grant application form PHS 398 (revised 5/95). This form is available in at most institutional offices of sponsored research and 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: asknih@od.nih.gov. BUDGET INSTRUCTIONS 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: o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of seven modules ($175,000) direct costs per year may be requested and each applicant may request up to five years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e. the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the entire Proposed Project Period should be shown in the box provided. o BUDGET JUSTIFICATION - Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. - List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried) and provide a narrative justification for each person based on his/her role on the project. - Identify all consultants by name and organizational affiliation and describe the services to be performed. - Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. No specific costs for items or categories should be shown. o CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and indirect) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall $175,000 direct costs requested in the first year.". A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. o BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. - Complete the educational block at the top of the form page; - List current position(s) and those previous positions directly relevant to the application; - List selected peer-reviewed publications directly relevant to the proposed project, with full citation; - The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. o OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI staff if there is a possibility for an award. o CHECKLIST - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. 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. Sample budgets and justification page will be provided upon request or following the submission of a letter of intent. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. The RFA label available in the PHS 398 application kit 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 2 of the face page of the application form and the YES box must be marked. Send or deliver the completed application and three signed, exact photocopies of it to the following, making sure that the original application with the RFA label attached is on top: CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants) 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 be sent to the Dr. C. James Scheirer at the address listed under Letter of Intent. It is important to send these two copies at the same time as the original and three copies are sent to the Center for Scientific Review. Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by January 22, 1998. 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 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 NHLBI. Incomplete applications will be returned to the applicant without further consideration. If NHLBI staff determines that the application is not responsive to the RFA, it 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 NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non- competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be promptly notified. Review Criteria Criteria for the scientific and technical merit review are as follows: Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-intergrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigator: Is the investigator appropriately trained and well- suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? Budget: Is the requested budget and estimation of time to completion of the project appropriate for the proposed research? The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. The roster of the reviewers for this RFA may be found at: http://www.nhlbi.nih.gov/nhlbi/meet.htm Link:[ under Peer Review: Special Emphasis Panels (SEPs)]. AWARD CRITERIA The anticipated date of award is September 1998. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Designated funding levels are subject to change at any time prior to award, due to unforeseen budgetary, administrative and/or scientific developments. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding this programmatic issues may be directed to: Dr. Luiz H. Barbosa Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10146 Bethesda, MD 20892-7950 Telephone: (301) 435-0075 FAX: (301) 480-0868 Email: lb30o@nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane R. Davis Grants Management Office National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20897-796 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: jane_davis@nih.gov AUTHORITY AND REGULATIONS The programs of the Division of Blood Diseases and Resources, NHLBI, are described in the Catalog of Federal Domestic Assistance Number 93.839. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to 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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