IMPROVING DNA, RNA AND PROTEIN AVAILABILITY IN FIXED TISSUE Release Date: March 23, 2000 PA NUMBER: PAR-00-079 National Cancer Institute Letter of Intent Receipt Dates: June 14, 2000 and February 9, 2001 Application Receipt Dates: July 19, 2000 and March 16, 2001 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 The application of many molecular technologies currently requires access to fresh or frozen tissue specimens because of the limited ability to extract sufficient high quality RNA or protein from fixed tissue. Progress toward clinical application of potentially useful molecular technologies is also hampered by fixation methods that fail to conserve the structure of nucleic acids and proteins in tissues. This initiative would encourage research to develop (1) new fixation methods to better preserve macromolecules and (2) methods to reverse the effects of formalin fixation to make nucleic acids and proteins more readily accessible in archived specimens. A better understanding of the physical and chemical basis of tissue preservation is vital for the rational development of new fixation methodologies. Knowledge of the mechanism of action of existing fixatives may provide insight that will allow simple modification of current techniques or development of new approaches that will meet the needs of both pathologists and researchers. In addition, carefully designed systematic studies may produce empirical solutions that will have the same end result. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA, Improving DNA, RNA and Protein Availability in Fixed Tissue, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. 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) exploratory/ developmental (R21) grant mechanism. This mechanism is utilized for pilot or feasibility studies to support exploratory research that may lead to innovative advances in science. Because the R21 grant mechanism is designed to support pilot studies, extensive preliminary data as evidence of feasibility are not required. However, the applicant must develop a sound research plan based on a strong scientific rationale. The R21 grant mechanism provides limited funds for short term (up to two years) research projects. The overall size of the budget should be proportional to the scope of research proposed. Budgets must be requested in $25,000 increments. The total direct costs requested may not exceed $100,000. If a subcontract is necessary the total direct costs requested, including the subcontract F&A costs may be up to $125,000. 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. These grants are non-renewable and continuation of projects developed under this PA will be through the traditional unsolicited investigator initiated grant program. 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 https://grants.nih.gov/grants/funding/modular/modular.htm RESEARCH OBJECTIVES Improved access to adequately preserved tissue is critical to facilitating studies to translate promising comprehensive molecular technologies into medical practice. Two major goals of this program announcement are: (1) to develop novel, improved methodologies for tissue preservation, and (2) to develop methods to reverse the effects of formalin fixation on RNA and proteins to allow the effective use of existing tissue archives in molecular studies. The lack of information about fundamental molecular interactions during fixation and the need to make tissue specimens more available for molecular studies argue strongly for an effort to encourage groups of pathologists, chemists, materials scientists and/or molecular biologists to work together to develop new approaches to fixation. These new methods should preserve macromolecules while at the same time maintaining appropriate morphology required for high quality diagnostic evaluation of specimens. Research proposed in response to this PA must be clearly focused on understanding the molecular principles of fixation. To achieve this goal, appropriate collaborations and interactions of chemists, biochemists and/or material scientists with molecular biologists and pathologists are strongly encouraged. Some examples of the types of studies that could be supported by this PA include but are not limited to: 1) Studies to better understand the basic mechanisms of fixation, with the ultimate goal of developing practical approaches to improve the availability of high quality DNA, RNA or protein from fixed tissue. 2) Studies to understand the impact of tissue handling during fixation. Such studies could evaluate the effects of heat, oxygen, diffusion rates and the penetration of fixatives into tissues and identify the major factors that affect the stability of macromolecules. 3) Studies to determine the importance of cross-linking in the stable morphological preservation of formalin fixed tissue. 4) Studies of methods to disrupt cross-links to free DNA, RNA and proteins. Approaches could include developing chemical reagents to remove cross-links in existing archival tissues or strategies to produce cross-links with cleavable groups to facilitate reversal. 5) Studies of the usefulness of enzyme inhibitors to stabilize nucleic acids and proteins in fixed tissues. 6) Studies to evaluate the impact of current embedding procedures on the integrity of macromolecules in fixed tissue. 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 have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994 available on the web at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not94-100.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 clear and compelling 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: https://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit 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 PA 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 NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Ms. Marianna J. Bledsoe, M.A., National Cancer Institute, at the address listed under INQUIRIES, by the letter of intent receipt date listed. APPLICATION PROCEDURES 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. Applications kits 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 title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. For those applicants with internet access, the 398 kit may be found at: https://grants.nih.gov/grants/forms.htm. Applicants are strongly encouraged to call the program contacts listed under INQUIRIES with any questions regarding their proposed project and the goals of this PA. BUDGET INSTRUCTIONS Modular Grant applications submitted in response to this PA will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year or up to a total direct cost of $125,000, including subcontract F&A costs.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 FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) 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 https://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 domestic or foreign. 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: https://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. 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. Applications not conforming to these guidelines will be considered unresponsive to this PA and will be returned without further review. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). Application kits 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, E-mail: grantsinfo@nih.gov. The title and number of the announcement must be typed in Section 2 on the face page of the application and the Yes box must be marked. For those applicants with internet access, the 398 kit may be found at https://grants.nih.gov/grants/forms.htm. All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-004.html). Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided 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) Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 - MSC 7710 Bethesda, MD 20892-7710 (20817 for express service) At the time of submission, two additional copies of the application must be sent to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8062, MSC-8239 Bethesda, MD 20892-8239 Rockville, MD 20852 (express courier) The two initial receipt dates for this initiative are listed at the beginning of this PA. It is anticipated that additional receipt dates will be announced at a later time. 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. 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 by the CSR for completeness and by the NCI program staff for adherence to the guidelines of this PA. Incomplete applications will be returned to the applicant without further consideration. Applications that are complete and adhere to the guidelines of this PA will be reviewed for scientific and technical merit by a committee convened by the NCI Division of Extramural Activities in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique. The applications may also 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 National Cancer Advisory 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. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and 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: Marianna Bledsoe, M.A. Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 700 6130 Executive Boulevard Bethesda, MD 20892-7399 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-7147 FAX: (301) 402-7819 Email: mb80s@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen Shino Grants Administration Branch National Cancer Institute Executive Plaza South, Suite 243 6120 Executive Boulevard Bethesda, MD 20892-7150 Telephone: (301) 496-8635 FAX: (301) 496-8601 Email: shinok@gab.nci.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.394, 93.395. 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 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.
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||