EVOLUTIONARY MECHANISMS IN INFECTIOUS DISEASES Release Date: August 18, 1999 PA NUMBER: PA-99-147 National Institute of General Medical Sciences National Institute of Dental and Craniofacial Research 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 goal of the program announcement is to encourage development of a predictive science of infectious diseases by applying the perspectives, theories, and methods from evolutionary biology to important issues of disease emergence, prevention and the consequences of treatment. Research projects involving interdisciplinary collaborations are an explicit goal of this program announcement. Approaches might include, but are not limited to, microbiology, population dynamics, chemistry, biochemistry, and computational biology. The focus is limited to discovery of fundamental biological principles rather than on detailed knowledge or treatment of specific diseases. 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 PA, Evolutionary Mechanisms in Infectious Diseases, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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 and local governments, and eligible agencies of the Federal Government. Foreign institutions are not eligible for program project (P01) grants. 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) research project grant (R01) and program project grant (P01) mechanisms. Supplements to existing NIH grants will also be considered. 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 five years. For R01 grants in requesting less than $250,000 in direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm RESEARCH OBJECTIVES Background A predictive science of infectious disease depends on our ability to anticipate with some confidence the behavior of host/parasite systems. Predictions might include when and where new infectious diseases will emerge, under what conditions drug resistance will arise, the consequences of therapeutic interventions, and the impact of ecological changes. Infectious systems consisting of parasite(s), vector(s), and host(s) are subject to dynamic interactions at many levels. For example, the ability of an infectious species to colonize plant or animal hosts, to proliferate, to cause disease, and to spread depends on a variety of factors, such as its genetic characteristics, its life history, and its mode of transmission, all of which are subject to evolutionary change. The ability of a host species to prevent, control, and/or promote interactions similarly depends on its innate defense system (including immune defenses), its behavior, its environment, and human intervention. Population dynamics, including population density, migration, population subdivision, and competition for resources, affect the evolution of pathogens, vectors and hosts. Evolutionary biology, molecular biology, genetics, systematics, chemistry, biochemistry, mathematics, and other disciplines, will contribute significantly to the development of a predictive science of infectious systems. For example, identifying the origins and host ranges of infectious agents requires a variety of molecular, genetic, mathematical, and evolutionary tools. Intervention to prevent or treat infections by behavior modification, control of vectors, vaccination, drug therapy or other means influences a variety of dynamic evolutionary processes in individual hosts, communities of hosts, and communities of pathogenic organisms. Understanding the conditions under which interventions fail (e.g., antibiotic resistance or reversion of live vaccines to virulence) and designing protocols to prevent these failures requires application of evolutionary understanding and the complexity of chemical interactions. Multidisciplinary approaches are essential for anticipating the conditions under which new infectious diseases will emerge and old ones will re-emerge. Although there is widespread interest in understanding, preventing, and treating infectious diseases and anticipating their emergence and re- emergence, research into evolutionary aspects of infectious systems has been limited. With a few exceptions, broadly interdisciplinary approaches are rarely employed in infectious disease research or in the design of protocols to prevent and treat infections. The goal of this initiative is to remedy this situation by supporting collaborations among scientists with diverse areas of expertise. Scientific Objectives Applications for research projects responsive to this program announcement should address broad evolutionary questions that are relevant to infectious diseases in general. Because host/parasite and other symbiotic systems exhibit a continuum of behavior, ranging from beneficial to pathological associations, general evolutionary principles can be expected to emerge from studies using a variety of models. For example, plant and microbial systems will be considered when they are used to address fundamental mechanisms of evolution. Human studies are included when the goal of the research is basic knowledge of the evolution of infectious systems rather than a specific disease entity. Studies that combine quantitative, theoretical, and experimental approaches are especially encouraged. Applicants must clearly explain how the proposed approaches and perspectives are expected to contribute to development of a predictive science of infectious diseases. Within the areas of investigation described below, relevant applications could focus on, but are not limited to, one or more of the following aspects: 1. Causes and sources of infectious diseases. o Genetic variation and structure of pathogen populations and the genetic relationships between commensal and pathogenic members of closely related taxa o Population analyses of the contributions and sources of the vertical and horizontal transfer of genes and accessory elements coding for virulence determinants, host range and specificity, and drug resistance o Genetic factors (pathogen, host or vector) responsible for geographic and temporal variation in disease frequency and severity 2. Interactions between hosts and pathogens. o Contribution of population dynamic and evolutionary processes to the pathogenesis and virulence of infecting organisms o Establishment of model systems to explore the relationship between the evolution of pathogenic organisms and factors affecting host susceptibility, including ecological, social and other environmental factors o Mechanisms of chemical signaling and communication 3. Consequences of intervention strategies. o Within-host population dynamics related to intervention strategies, including reversion to virulence of live vaccines (as opposed to outgrowth of existing unattenuated organisms), as well as evolution of resistance following antimicrobial drug therapy or vaccination o Establishment of model systems (either in vitro systems, or in vivo systems involving non-human pathogens and/or animal, microbe, or plant hosts) to predict the ecological and evolutionary consequences of programs involving host behavior, vaccination, antimicrobial drug therapy, and other intervention strategies on pathogen, host, and vector populations o Novel mechanisms of antibiotic action o Use of evolutionary approaches to create new strategies for drug development and delivery o Identification of new resistance mechanisms, including how they arose 4. Establishment of model systems to explore the environmental, physiological and genetic factors responsible for generating and maintaining variation in pathogen, vector, and host populations, including co-evolutionary dynamics. 5. Natural history of pathogenic organisms. o Evolutionary basis for the normal range of pathogen habitats and hosts o Establishment of model systems to explore the molecular basis of host barriers that must be overcome by pathogens in order to extend their ranges o Establishment of model systems to explore the molecular, individual, and population dynamics of extending the niche or host range of a pathogen. 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 28, 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research 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: [email protected]. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html MODULAR GRANT INSTRUCTIONS FOR R01 GRANTS REQUESTING LESS THAN $250,000 DIRECT COSTS PER YEAR. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application 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: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, List key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the letter of intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. R01 applications that request more than $250,000 direct costs per year should follow the instructions in the PHS Form 398. 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. 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (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)? Are the nature and quality of the collaborations appropriate for the proposed research? (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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o 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. The initial review group will also examine the provisions for the protection of human 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: Irene Anne Eckstrand, Ph.D. Division of Genetics and Developmental Biology National Institute of General Medical Sciences Building 45, Room 2AS.25K, MSC 6200 Bethesda, MD 20892-6200 Telephone: (301) 594-0943 FAX: (301) 480-2228 Email: [email protected] Dennis Mangan, Ph.D. Division of Extramural Research National Institute of Dental and Craniofacial Research Building 45, Room 4AN.32F, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-2421 FAX: (301) 480-8318 Email: [email protected] Direct inquiries regarding fiscal matters to: Ms. Marcia Cohn Grants Management Office National Institute of General Medical Sciences Building 45, Room 2AN.44E Bethesda, MD 20892-6200 Telephone: (301) 594-3918 FAX: (301) 480-1969 Email: [email protected] Daniel Milstead Division of Extramural Research National Institute of Dental and Craniofacial Research Building 45, Room 4AN.44, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-4800 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.862. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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, and 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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