COMPETING SUPPLEMENTS FOR ORGANOTYPIC MODELS OF CANCER RELEASE DATE: January 29, 2002 PAR NUMBER: PAR-02-052 EXPIRATION DATE: This Program Announcement expires on March 29, 2002, unless reissued. PARTICIPATING INSTITUTES AND CENTERS (ICs): National Cancer Institute (NCI) (http://cancer.gov) Application Receipt Date: March 28, 2002 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 An important class of mammalian models with considerable potential for cancer research is one in which the multiple cell types from a particular tissue are studied together, as reconstituted multi-cellular systems, or as tissue explants in culture or in animals as transplants. However, such model systems are often insufficiently developed or under-utilized. The intent of this program announcement is to encourage NCI-funded investigators to explore the development and use of alternate model systems that more closely resemble normal tissue or emerging tumors than do dispersed cells cultured on plastic. RESEARCH OBJECTIVES Background Mammalian model systems comprised of the multiple cell types from a particular tissue may be reconstituted or transplanted in culture or into appropriate live animal hosts. Sufficient advances in tissue engineering and gene delivery technologies make it feasible to use multi-cell systems to explore some of the questions normally pursued with in vivo models. Some examples are the role of specific cell types and their interactions, effects of alterations in particular genes or factors, or interactions between genes and endogenous factors in the genesis and progression of cancer from specific cell types. This warrants development of alternate systems that more closely resemble normal tissue or developing tumors than do dispersed cells cultured on plastic. There are a number of possible approaches to the design and use of organotypic cultures. For example, in one published study, a model system of spontaneously immortalized human keratinocytes recapitulated the three- dimensional micro-environment and epithelial-mesenchymal interactions of human stratifying epithelium. Exposure of the model system to 2,3,7,8- tetrachlorodibenzo-p-dioxin altered normal skin homeostasis exclusively by effects on the keratinocyte differentiation program, resulting in profound changes in tissue architecture. Another recent study used a human papilloma virus (HPV)-infected human cervical cancer cell line grown as a "raft" culture. Only is this culture system, which has a tissue architecture that closely resembles the cervix, did the cancer cell line duplicate the entire HPV cell cycle, even producing infectious viral particles. Superinfection with adeno-associated virus (AAV) reduced HPV replication, and caused significant changes to epithelial morphology consistent with the ability of AAV to interfere with development of cervical carcinoma. Another similar raft culture of human keratinocytes was used to delineate many of the elements that restrict adenovirus replication to cells expressing the E6 and E7 genes of HPV to enable delivery of gene therapy exclusively to tumor cells. Further examples include organotypic cultures of brain slices and human duodenal mucosa. In the former instance, biolistic gene delivery was used to define the neuronal cell expression patterns of promoter deletion constructs of two specific genes, providing important preliminary results to delineate the design of gene constructs for promoter studies in transgenic models. In the latter case, the human duodenal organ cultures were used to verify the cell-type source and mechanisms of action of particular cytokines in regulation of cell proliferation, apoptosis, and differentiation in human small intestinal epithelium. Summary The goal of this PA is to encourage the design and use of organotypic cell cultures. These systems may be used to delineate the roles of the different cell types in a tissue or organ, define their interactions, and study the contribution of normal or mutated phenotype of each to tumors that arise in that organ. The cells themselves may be normal, tumor-derived, or genetically engineered, and used in various combinations. Organotypic models may provide alternatives to cell culture models that are currently used for a variety of research applications, for example, to screen molecularly targeted therapy or test delivery strategies for new agents. They may pave the way for derivation of additional animal models of epithelial malignancies that alter the types of cells found in the tissue stroma. MECHANISM OF SUPPORT This PA will use the NIH competing supplement mechanism to ongoing NCI R01, P01, or U01 grants. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The total project period for an application submitted in response to this PA may not exceed the project period of the parent grant. Direct costs for the supplement may not exceed $50,000/year. This PA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). 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 o Faith-based organizations 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 Grants that are eligible for supplementation in response to this program announcement are NCI-funded R01, P01, and U01 grants whose project end dates are 04/30/04 or later. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Suresh Mohla, Ph.D. Division of Cancer Biology National Cancer Institute Executive Plaza North, Suite 5000 Bethesda, MD 20892 Telephone: (301) 435-1878 FAX: (301) 480-0864 Email: sm82e@nih.gov o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncidearefof@mail.nih.gov o Direct your questions about financial or grants management matters to: Ms. Dena Solomon Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7208 FAX: (301) 496-8601 Email: ds86p@nih.gov APPLICATION PROCEDURES 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 GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted by the receipt date listed at the beginning of this program announcement. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs 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. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html). This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received by the date listed on the first page of this PA. 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 Upon receipt, applications will be reviewed for completeness by the CSR and the NCI program staff for adherence to the guidelines of this PA. Applications not adhering to the guidelines of this PA, and those applications that are incomplete as determined by CSR or by NCI program staff, will be returned to the applicant without review. 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 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 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) 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 Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines. 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://grants.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. 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. 93.396, 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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