MATHEMATICAL MODELS OF CYTOKINE/CHEMOKINE NETWORKS IN HIV ASSOCIATED LUNG DISEASE Release Date: December 6, 2001 RFA: RFA-HL-02-009 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) National Institute of Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib.nih.gov) Letter of Intent Receipt Date: March 12, 2002 Application Receipt Date: April 12, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The objective of this Request for Applications (RFA) is to stimulate research on the development and validation of mathematical models of cytokine/chemokine networks involved in the pathogenesis of human immunodeficiency virus type 1 (HIV-1)- associated lung disease. This RFA encourages the use of computational biological methods to create mathematical models of cytokine/chemokine networks (e.g., using nonlinear mathematical techniques) and innovative collaborations between biomathematicians, clinical investigators, and bench scientists. An important aspect of this program will be formation of collaborations to validate the mathematical models using biological experimentation systems. Another important goal is to attract junior level mathematicians and quantitative biologists into this area of biological research. To facilitate their participation the Mentored Quantitative Research Career Development Award (K25) has been included as one of the mechanisms of support under this RFA. Among the disciplines and expertise that may be appropriate for this research program are mathematical modeling, bioinformatics, computer programming, biostatistics, pathogenesis of infections, immunology, lung cell biology, molecular biology, virology, bacteriology, mycology, genetics, infectious diseases, lung pathology, pulmonology, and veterinary medicine. 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 Request for Applications (RFA), "Mathematical Models of Cytokine/Chemokine Networks in HIV Associated Lung Disease," 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/. ELIGIBILITY REQUIREMENTS R01 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. Domestic institutions only, may submit applications for K25 awards. In addition, for K25 applications, former principal investigators on NIH research project (R01), program project (P01), center grants, (P50, P60), FIRST Awards (R29), SBIR/STTR awards, sub-projects of program project or center grants, K01, K08 or K23 awards, or the equivalent are not eligible. Former principal investigators of an NIH Small Grant (R03) or Exploratory/Developmental Grants (R21) remain eligible. A candidate for the Mentored Quantitative Research Career Development Award may not concurrently apply for any other PHS award that duplicates the provisions of this award nor have another application pending award. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) and the Mentored Quantitative Research Career Development Award (K25) mechanisms of support. A description of the K25 award is available on the web at: http://grants.nih.gov/grants/guide/pa-files/PA-99-087.html. Individuals may apply for either an R01 grant or a K25 award under this RFA, but cannot apply for both grants. Each application submitted for this RFA must be a complete, independent entity and not depend on any other application submitted in response to this RFA. Responsibility for the planning, direction, and execution of each of the proposed projects will be solely that of the respective applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2002. Although multidisciplinary approaches are encouraged, it is not the intent of this RFA to solicit applications for large studies encompassing a variety of individual subprojects, i.e., program projects. If collaborative arrangements through subcontracts with other institutions are planned, consult the program staff listed under INQUIRIES. Biomedical investigators without prior R29 or R01 support are encouraged to apply for R01s under this RFA and to identify their status on the front of the grant application. 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 should be included with the application. FUNDS AVAILABLE It is anticipated that for fiscal year 2002, approximately $3.0 million, total costs, will be committed by NHLBI and $250,000, total costs, will be committed by NIBIB, for this RFA. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that up to 8- 10 new R01 grants will be awarded under this program and up to 2-4 new K25 grants will be awarded under this program. The specific numbers to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. 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 RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. For this RFA, funds for R01s must be requested in $25,000 direct cost modules and a maximum of 12 modules ($300,000 direct costs) per year may be requested unless the investigators are working with non-human primate models in which case a maximum of 18 modules ($450,000 direct costs ) per year may be requested. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budgetary information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. For the K25 grants funded under this RFA, funding is determined by the allowable costs designated for the K25 type of award, salary of up to $75,000 per year plus fringe benefits and research development support of up to $40,000 per year for the following expenses: (a) tuition, fees, and books related to career development, (b) research expenses, such as supplies, equipment and technical personnel, c) travel to research meetings or training, (d) research support services including personnel and computer time. Ancillary Personnel Support: Salary for mentors, secretarial, and administrative assistance etc., is not allowed. Facilities and Administrative costs will be reimbursed at 8 percent of modified total direct costs. RESEARCH OBJECTIVES Background The cytokine/chemokine environment in the lung influences the ability of HIV-1 to infect, replicate and evolve in lung cells. Once present in lung cells (mostly alveolar macrophages) HIV-1 profoundly changes their ability to produce and respond to inflammatory mediators, which alters local immune responses. A better understanding of the complex and redundant chemokine/cytokine networks in the lung is needed to understand the pathogenesis of HIV-1 in the lung, the pathogenesis of HIV-1-related lung infections due to other viruses, bacteria, and fungi, and changes brought about by the reconstitution of immunity during highly active antiretroviral therapy (HAART). Mathematical models are likely to help in this endeavor. Numerous cytokine studies have taught us that manipulating a single interaction in the context of complex networks can lead to unexpected and often undesirable results. Nonlinear mathematical models of cytokine/chemokine systems may aid in understanding the consequences of manipulating particular system components. Most current studies follow events over a period of weeks, but the most crucial changes may be occurring during the first few minutes. One could attempt to model the timing of events associated with cytokine release and activity, cytokine concentrations and precursor cell populations, and attempt to predict what type of responses might occur. Mathematical models could be used to help generate and test new hypotheses. They could help explore and test new approaches to drug and immunomodulatory therapy that minimize the harmful aspects of HIV infection and host responses to HIV-associated infections, such as P. carinii pneumonia and tuberculosis. Mathematical models based on available knowledge of cytokine/chemokine networks may provide insight into interactions involving these mediators, other components of the immune system, and microbes. The mathematical models could be used to compare and contrast existing controversies and extend intuition about biological processes. Computational models would offer new approaches to elucidating these complex reaction series, generating hypotheses, and clarifying existing data and theories. Creating the models will require close collaborations between clinicians, bench scientists and biomathematicians and when successful, as for example in the case of apparently chaotic cardiac arrhythmias, can be quite helpful in revealing underlying mechanisms and pathologies. Models based on differential equations could include parameters of key processes, for example, rate constants, sensitivity and uncertainty analyses, and bifurcations. The models could easily be perturbed. Once developed the models could allow ideas to be explored quickly and inexpensively. Some limitations of using models are that answers derived from them are based on the original assumptions and that validation of the models may be difficult to achieve. Models for control strategies of TB epidemics and models to understand the dynamics of HIV infection including, production, turnover, half-life, and possible reservoirs of infection have been developed. Modeling HIV changed concepts about viral growth and lead to the realization of the highly dynamic growth of the virus. Mathematical models might be useful in examining specific issues related to the pathogenesis of HIV-1 in the lung, including the following examples. Virus load in the lung is low early in disease, but rises significantly during the later stages of disease. There is also a significant increase in pulmonary lymphocytosis, mainly due to CD8 cells. It is not known if CD8 cells, which suppress HIV-1 in a non-specific manner, exert control over virus populations through chemokine production, and how this might balance with virus-enhancing cytokines. Three chemokines (MIP-1a, MIP-1 , and RANTES) are largely responsible for HIV-1 suppression, but inhibit only M-tropic strains. These three chemokines are also ligands for the M-tropic cofactor CCR5. The chemokine ligand for CXCR-4 (SDF) blocks infection by T-tropic strains, but its role in regulation of virus replication is unknown. Objectives and Scope The purpose of this RFA is to stimulate research on the development and validation of mathematical models of cytokine/chemokine networks involved in the pathogenesis of human immunodeficiency virus type 1 (HIV)-Associated Lung Disease. In particular this program encourages the use of computational biological methods to create mathematical models of cytokine/chemokine networks. The use of nonlinear mathematical techniques is of particular interest. The formation of collaborations between biomathematicians, clinical investigators, and bench scientists to validate the mathematical models using biological experimentation systems are strongly encouraged. Another important aspect of this program will be attracting junior level mathematicians and other quantitative scientists into this area of biological research. To facilitate their participation the Mentored Quantitative Research Career Development Award (K25) has been included as one of the mechanisms of support under this RFA. Mathematical models are needed to improve our understanding of the basic mechanisms of HIV-1 disease in the lung and expedite development and testing of new hypotheses. Cytokine/chemokine networks are crucial in mediating HIV-1- associated inflammatory reactions and infections in the lung, but they are extremely complex and redundant, making it very difficult to learn about the consequences of perturbations to any part of the system. The cytokine/chemokine environment in the lung influences the ability of HIV to infect, replicate and evolve in lung cells. HIV-1 profoundly changes the ability of lung cells to produce and respond to inflammatory mediators and alters local immune responses. Better knowledge of chemokine/cytokine networks in the lung is needed to understand HIV-1 induced lung injury, HIV-1- related lung infections due to other viruses, bacteria, and fungi and changes brought about by the reconstitution of immunity during highly active antiretroviral therapy (HAART). This RFA program is particularly relevant to African American and Hispanic minority populations who are disproportionately affected by the HIV-1 epidemic in comparison to the total population. In responding to this RFA expertise might be needed in the following areas: mathematical modeling, bioinformatics, computer programming, biostatistics, pathogenesis of infections, immunology, lung cell biology, molecular biology, virology, bacteriology, mycology, genetics, infectious diseases, lung pathology, pulmonology, epidemiology, and veterinary medicine. This RFA is co-sponsored by NHLBI and NIBIB. NHLBI is interested in encouraging research on using mathematical approaches to understand the role of cytokine/chemokine networks in the pathogenesis of HIV infection and HIV-1- associated infections in the lung. Whereas, NIBIB is particularly interested in using this RFA to encourage the training of young biomathematicians and bioengineers and is primarily interested in sponsoring mentored career development awards (K25) under this program. Bringing young mathematicians and other quantitative scientists into this area of research is of great interest to both institutes and NHLBI may also sponsor mentored research under this program. Some examples of areas of research that might be included under this RFA are as follows: o What determines whether pulmonary inflammation or immune incompetence predominates. This likely involves both pro- and anti-inflammatory cytokine networks in the lung. o CD4 is the principal receptor for HIV entry and infection of target cells, but chemokine receptors are required, in conjunction with CD4, for HIV entry and infection. These molecules normally function to induce signals mediated by chemokines, which are a family of protein cytokines. T-tropic isolates utilize the chemokine receptor CXCR-4 as a cofactor for entry, M-tropic strains use CCR5. Many other chemokine co-receptors are being discovered, but little is known about their function and distribution. Signaling through the receptor is not needed for HIV entry, but it is not known whether HIV interaction with the receptors can initiate signaling, and whether this may contribute to cellular dysfunction. o What factor(s) lead to enhanced virus replication in late stage disease or, conversely, what factors might restrict virus but be lost as time goes on. Cytokine-mediated mechanisms may be among the factors that upregulate and limit viral growth. o The role of chemokines/cytokines in the pathogenesis of HIV-1-associated pulmonary co-infections, e.g. tuberculosis, P.carinii pneumonia and other bacterial and fungal pneumonias. o The role of chemokines/cytokines in the activation of HIV-1. These are examples only. Investigators should not feel limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. Two additional goals of the RFA specific to the Mentored Quantitative Research Career Development Award, K25 awards, are as follows: o Encourage research-oriented quantitative scientists and engineers with little or no experience in biology or biomedicine to develop independent research skills and gain experience in advanced methods and experimental approaches that will allow them to conduct basic or clinical biomedical research related to cytokine/chemokine networks in HIV-associated lung disease or to play leading roles in multi-disciplinary research teams. o Increase the pool of quantitative researchers who can conduct biomedical research related to the genetic aspects of tuberculosis in the lung, capitalizing on the quantitative backgrounds of the investigators to inform new directions in this area of research. SPECIAL REQUIREMENTS To be responsive to the RFA, applications must include plans and the necessary mathematical expertise to develop mathematical models of cytokine/chemokine networks in the lungs and address HIV or HIV-related disorders. We are particularly interested in non linear models. To the extent possible the models should be tested and validated. Applicants are strongly encouraged to include a major biological component. It is anticipated that close collaborations between mathematicians, bench scientists, clinical investigators, or epidemiologists will be needed. Multidisciplinary approaches that include biologic validation of the mathematical models are of particular interest. Research in animal models is encouraged. The mathematical models may address cytokine/chemokine networks in the lung during HIV infection in humans or animal models of HIV infection (e.g. SIV infection, mouse models immunodeficient states). Also responsive, are mathematical models of cytokine/chemokine networks in the lung involved in the pathogenesis of diseases frequently associated with HIV, including, but not limited to tuberculosis, Pneumocystis carinii pneumonia, and cryptococcosis. The cytokine/chemokine network models may also address interactions between HIV and other factors in the lung. Examples include, but are not limited to HIV-tuberculosis interactions, HIV-cigarette smoke interactions, HIV- pneumococcal pneumonia interactions, and lung reactions that occur during the treatment of HIV infection with antiretroviral agents. Grant applications that only address cytokine/chemokine networks in normal lungs are not acceptable, but may be used for comparisson. Research on human tissue is encouraged. However, large clinical or population based studies are not within the scope of this RFA. Each application submitted for this RFA must be a complete, independent entity and not depend on any other application submitted in response to this RFA. K25 applicants must fulfill the eligibility requirements for the K25 award described at http://grants.nih.gov/grants/guide/pa-files/PA-99-087.html. Special requirements for the K25 award pertain to the candidate, the mentor(s), the program, the environment and possible future evaluations. Upon initiation of the program, the NHLBI and NIBIB will sponsor periodic meetings to encourage exchange of information among all funded investigators who participate in this program. A major goal of these meetings is to facilitate progress by providing a forum that will lead to sharing ideas, technology, data, skills, and biological materials. Applicants for both K25 and R01 awards must budget for travel funds that will allow principal investigators and other key research scientists to participate in these meetings. The meetings are usually one day meetings, held each year, in Bethesda, Maryland. Applicants must include a statement in their applications indicating their willingness to participate in these 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 sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://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. 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. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by March 12, 2002, 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. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NHLBI staff to begin to identify appropriate reviewers, to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Deborah P. Beebe listed under INQUIRIES by the letter of intent date listed. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) available at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. Modular grant applications will request direct costs in $25,000 modules, up to a total direct cost of $300,000 (12 modules) per year for all R01s. Investigators working with non human primate models may submit modular grant applications (using $25,000 modules) for up to $450,000 (18 modules) direct costs. Specific Instructions for K25 Applications An important goal of this RFA is to stimulate collaborations between quantitative scientists and biological scientists to investigate the genetics of tuberculosis. We want to encourage junior level quantitative biologists to do research on the mathematical models of chemokine/cytokine networks in HIV- associated lung diseases. For this reason the K25 program, which fosters career development of mathematicians and engineers interested in biomedical research, has been included as a funding mechanism under this RFA. Some information on eligibility criteria for the K25 is summarized below. However, THOSE INTERESTED IN APPLYING FOR K25 AWARDS WILL NEED TO OBTAIN ADDITIONAL INFORMATION ON THE K25 GOALS, ELIGIBILITY, RESTRICTIONS AND SPECIAL REQUIREMENTS FROM THE K25 PROGRAM ANNOUNCEMENT, WHICH CAN BE FOUND AT: http://grants.nih.gov/grants/guide/pa-files/PA-99-087.html. The K25 awards are NOT modular. Applications for K25 awards under this RFA must use the RFA receipt date of April 12, 2002, NOT the application receipt dates stated in the PA-99-087. The K25 application budgets should be prepared in accordance with the allowable costs and instructions provided in PA-99-087. The K25 applications must follow the K25 guidelines and comply with the requirements for the K25. Just-in-time instructions apply to both the R01 and K25 mechanisms. o Special eligibility requirements apply to K25 Candidates applying for this RFA: They must have demonstrated research interests with an advanced degree in a quantitative area of science or engineering: M.S.E.E., Ph.D., D.Sc., etc. They must identify a mentor with extensive biomedical and/or computational biology research experience. The K25 candidates must be willing to spend at least 75 percent of full-time professional effort conducting research career development and basic or clinical research. K25 applicants experience in biomedical research may vary. Some may have very limited experience in biomedical research and require didactic training and a very closely supervised research experience. Other K25 applicants, with more experience, may require less class work and less supervision. Applications may be submitted on behalf of candidates, by DOMESTIC organizations, public or private, such as research foundations, research institutions, commercial entities, medical, dental, or nursing schools, Federal National Laboratories (except for laboratories of the National Institutes of Health), or other institutions of higher education. At time of the K25 AWARD, CANDIDATES MUST BE CITIZENS OR NONCITIZEN NATIONALS OF THE UNITED STATES, OR HAVE BEEN LAWFULLY ADMITTED TO THE UNITED STATES FOR PERMANENT RESIDENCE (I.E., IN POSSESSION OF A CURRENTLY VALID ALIEN REGISTRATION RECEIPT CARD I-551, OR OTHER LEGAL VERIFICATION OF SUCH STATUS). Noncitizen nationals are generally persons born in outlying possessions of the United States (i.e., American Samoa and Swains Island). Individuals on temporary or student visas are not eligible. o FORMER PRINCIPAL INVESTIGATORS on NIH research project (R01), program project (P01), center grants (P50, P60), FIRST Awards (R29), SBIR/STTR awards, sub-projects of program project or center grants, K01, K08 or K23 awards, or the equivalent are NOT ELIGIBLE FOR THE K25 AWARD. FORMER PRINCIPAL INVESTIGATORS of an NIH Small Grant (R03) or Exploratory/Developmental Grants (R21) REMAIN ELIGIBLE. A candidate for the Mentored Quantitative Research Career Development Award may not concurrently apply for any other PHS award that duplicates the provisions of this award nor have another application pending award. Mentored Quantitative Research Career Development Award recipients are strongly encouraged to apply for independent research grant support, either Federal or private, during the latter period of this K25 award. However, since the K25 is a full professional effort award, time conducting additional research directly related to this award is subsumed under the salary support already provided by this award. The K25 Application Must Contain the Following: Candidate (K25) o A description of the candidate"s commitment to a career in quantitative biomedical, behavioral, or bioengineering research o Evidence of the candidate"s interest in conducting research o Evidence of the candidate"s potential to develop into an independent investigator o A description of immediate and long-term career objectives, explaining how the award will contribute to their attainment o A commitment of at least 75 percent effort to this research program o Three sealed letters of recommendation addressing the candidate"s potential for a research career in quantitative biomedicine or bioengineering. The mentor"s statement (see below) should not be included as one of the letters of recommendation, although the mentor(s) may submit a separate letter(s) of recommendation. Career Development Plan (K25) o A description of the career development plan, incorporating consideration of the candidate"s goals and prior experience. It must describe a systematic plan to obtain the necessary theoretical and conceptual background, in addition to the research experience, necessary to launch an independent research career in quantitative biomedicine or bioengineering. o Candidates must describe the availability of courses important to their career development plan at their institution and the manner of integration of these studies into their career development plan. o The career development plan must be tailored to the needs of the individual candidate and the ultimate goal of achieving independence as a researcher in quantitative biomedicine or bioengineering. Less experienced candidates may require a phased developmental period in which the first one to two year(s) of the award are largely of a didactic nature followed by a period of intense, supervised research. Candidates with more experience at the time of application may need a shorter developmental period and may already have an adequate theoretical background. o Candidates must describe plans to receive instruction in the responsible conduct of research. These plans must detail the proposed subject matter, format, frequency, and duration of instruction. No award will be made if an application lacks this component. Research Plan (K25) o A description of the quantitative biomedical, behavioral, or bioengineering research plan. The research plan must be described as outlined in form PHS 398, including sections on the Specific Aims, Background and Significance, Progress Report/Preliminary Studies, Research Design and Methods. The candidate should consult with the mentor regarding the development of this section. Mentor"s Statement (K25) o The application must include information on the mentor(s), including information on basic or clinical biomedical research qualifications in the research area proposed by the candidate and previous experience as a research supervisor. The application must also include information to describe the nature and extent of supervision that will occur during the proposed award period. Mentors may be employed in any sector of the biomedical research community (e.g., academia, industry, non-profit research institutions). Environment and Institutional Commitment (K25) o The sponsoring institution must document a strong, well-established research and training program related to the candidate"s area of interest, including a high-quality research environment with staff capable of productive collaboration with the candidate. The sponsoring institution also must provide a statement of commitment to the candidate"s development into a productive, independent investigator. SUBMISSION PROCEDURES FOR ALL APPLICATIONS The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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 as well as all five collated sets of Appendix material must be sent to Dr. Deborah Beebe at the address listed under Inquiries. Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Applications must be received by the application receipt date listed in the heading of this RFA, April 12, 2002. 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. Principal investigators should not sent supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Deborah Beebe at the address listed under Inquiries. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness by the NHLBI and NIBIB. Incomplete and/or non-responsive applications 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. The roster of reviewers for the RFA will be available on the NHLBI home page approximately four weeks prior to the scheduled review date. As part of the initial merit review, a process will be used by the initial review group in which all applications 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council or the National Institute of Biotechnology and Bioengineering Advisory Council. Review Criteria for R01 Applications 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 review, comments on the following aspects of the application will be made 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)? (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? Review Criteria for K25 Applications The following review criteria will be applied: Candidate o Quality of the candidate"s academic and research record, o Potential to develop as an independent quantitative biomedical or bioengineering researcher or to play significant role in multi-disciplinary research teams, and o Commitment to a career in quantitative biomedical or bioengineering research. Career Development Plan o Likelihood that the career development plan will contribute substantially to the scientific development of the candidate, o Appropriateness of the content and duration of the proposed didactic and research phases of the award, o Consistency of the career development plan with the candidate"s career goals and prior research experience, and o Quality of the proposed training in responsible conduct of research. Research Plan Reviewers recognize that an individual with limited research experience is less likely to be able to prepare a research plan with the breadth and depth of that submitted by a more experienced investigator. Although it is understood that K25 applications do not require the level of detail necessary in regular research grant applications, a fundamentally sound research plan must be provided. In general, less detail is expected with regard to research planned for the later years of the award, but the application should outline the general goals for these years. o Appropriateness of the research plan to the stage of research development and as a vehicle for developing the research skills as described in the career development plan, o Scientific and technical merit of the research question, design and methodology, o Relevance of the proposed research to the candidate"s career objectives, o Adequacy of the plan"s attention to gender and minority issues associated with projects involving human subjects, and o Adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion. Mentor o History of research productivity and support in the area of basic or clinical biomedical research, o Appropriateness of mentor"s research qualifications in the area of this application, o Quality and extent of mentor"s proposed role in providing guidance and advice to the candidate, and o Previous experience in fostering the development of researchers. Environment and Institutional Commitment o Applicant institution"s commitment to the scientific development of the candidate and assurances that the institution intends the candidate to be an integral part of its research program, o Adequacy of research facilities and the availability of appropriate educational opportunities (including access to such facilities or opportunities in other institutions), o Quality and relevance of the environment for scientific and professional development of the candidate, and o Applicant institution"s commitment to an appropriate balance of research and other responsibilities. In addition to the above criteria, in accordance with NIH policy, all R01 and K25 applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research will be reviewed. 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. SCHEDULE Letter of Intent Receipt Date: March 12, 2002 Application Receipt Date: April 12, 2002 Review: June/July 2002 Council Review: September 5-6, 2002 Anticipated Start Date: September 30, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by the awarding Institutes in making funding recommendations. The Institutes may fund individual applications based on a number of considerations, the most important of which are based on their scientific merit and their importance in meeting the objectives of the RFA. Applications from new investigators will be strongly considered. INQUIRIES Inquiries concerning this RFA are strongly encouraged. Potential applicants should request a copy of the sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 E-mail: peavyh@nih.gov Or Sandra Colombini Hatch, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 E-mail: hatchs@nhlbi.nih.gov Or Joan T. Harmon, Ph.D. Division of Bioengineering National Institute of Biomedical Imaging and Bioengineering (NIBIB) Building 31, Room 1B37, MSC 2077 Bethesda, MD 20892 Telephone: (301) 451-6772 FAX: (301) 480-4515 Email: harmonj@nibib.nih.gov Direct inquiries regarding fiscal matters (e.g., sample budget pages) to: Raymond Zimmerman Division Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7158, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: ZimmermR@nhlbi.nih.gov Inquires regarding review, letters of intent and two copies of the grant application should be directed to: Deborah P. Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0270 FAX: (301) 480-3541 E-mail: beebed@nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, Nos. 93.838 and 93.361. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 UC241 and 284) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 72 and CFR 52 and 45 CFR Part 74 for NIAID. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a 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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