ASTHMA EXACERBATIONS: BIOLOGY AND DISEASE PROGRESSION RELEASE DATE: February 27, 2004 RFA Number: RFA-HL-04-029 EXPIRATION DATE: June 19, 2004 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) ( COMPONENT OF PARTICIPATING ORGANIZATION: National Heart, Lung and Blood Institute (NHLBI) ( National Institute of Allergy and Infectious Diseases (NIAID) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) No. 93.838, Lung Diseases Research No. 93.855, Immunology, Allergy and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research LETTER OF INTENT RECEIPT DATE: May 18, 2004 APPLICATION RECEIPT DATE: June 18, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA Asthma exacerbations are a major cause of morbidity and mortality in asthma and a significant concern for the clinical management of the disease. The National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID) invite applications, in clinical and basic research, that will elucidate the biologic mechanisms of asthma exacerbation pathobiology and resolution and their impact on lung function, physiology and disease state. RESEARCH OBJECTIVES Background Over the past two decades, the prevalence of asthma in the United States has more than doubled with over 14 million people now afflicted with this disease. Asthma exacerbations are a major cause of lost days from work and school, sleep disruption, restricted activities, physician and emergency room visits and asthma-related mortality. Additionally, management of disease exacerbations consumes a large proportion of the estimated annual 20 billion dollars that asthma costs the U.S. economy. Currently, we have little understanding of the pathophysiologic processes that occur during an exacerbation, how exacerbations resolve, the impact of exacerbations on future exacerbation severity and frequency, and what the long term impact of exacerbations is on lung physiology, function and disease progression. This information is critical for the development of more effective treatment modalities that will control symptoms and exacerbations while maintaining or improving lung function. In contrast to our understanding of the basic underlying inflammatory mechanisms of asthma pathogenesis, the mechanisms and consequences of exacerbations have not been well-studied and are poorly understood. The potential relationship between exacerbations and progressive loss of lung function needs to be explored and defined. Since exacerbations often occur while the patient is receiving treatment, it is likely that the mechanisms of these reactions are distinct from the processes in more stable disease. Many patients with asthma experience exacerbations which seem to resolve completely with periods of normal lung function in between each exacerbation. However, it is unclear whether changes in lung structure, function and immune response remain following exacerbations, setting the stage for future episodes, ultimately contributing to disease chronicity and persistence. Knowledge regarding resolution of exacerbations is particularly lacking. Research is needed which will define the pathways by which the immune response and subsequent inflammation are altered during resolution. Limited knowledge exists regarding: the initial signals that down regulate inflammation; regulatory cells, mediators and the mechanisms that effect down regulation; characterization of crosstalk between pathways responsible for immune response activation and termination; and termination of mechanisms which result in altered lung physiology and function such as mucus metaplasia, airway smooth muscle hypertrophy, damage to the bronchial epithelium, sub-epithelial collagen deposition and altered immune responsiveness. While current asthma treatments are effective at controlling initial inflammation, accumulating evidence suggests that certain aspects of the disease process are ongoing despite therapy. Additionally, there is an increasing awareness of subsets of asthma patients whose disease is not well-controlled with the use of currently available treatments. Elucidation of the mechanisms of the pathophysiology and resolution of exacerbations will provide the basis for development of interventions which will be able to target ongoing, downstream processes that result in altered immune response and airways physiology and function. Research Scope The objective of this RFA is to explore the underlying pathobiology and mechanisms of resolution of exacerbations; how these processes impact lung function and physiology during and after the exacerbation; and the relation of exacerbations to future frequency and severity of exacerbation and disease progression. Applicants are expected to define their exacerbation model and discuss the implications of the initiating trigger and how it relates to pathophysiology of exacerbation, if relevant. Studies may be conducted in either humans or animals; however, studies in human subjects are strongly encouraged. Basic studies must be able to relate proposed research directly to the questions posed above, in a relevant model. Programs that combine basic and clinical studies are desired. Intervention-based clinical trials and long-term epidemiology studies and studies focusing on exacerbation triggers are not appropriate for this RFA. Some examples of research areas appropriate for this RFA include, but are not limited to the following: o Identification of immune regulatory and effector cells and molecules which control inflammation during the active and resolution phases of exacerbations. o Characterization of interactions among immune cells, mediators and lung cells responsible for immune response activation and termination. o Characterization of the role of the innate immune system and interactions between innate and adaptive immune mechanisms during exacerbations. o Characterization of the role of apoptosis in termination of the pulmonary immune response during exacerbation resolution. o Delineation of alterations in lung function, airway structure and cellular composition, and neural control during exacerbation and resolution. o Characterization of genetic factors associated with frequency and/or severity of exacerbation. o Utilization of state-of-the-art imaging techniques to gain knowledge regarding effector pathways and cells involved in exacerbation and resolution and assessment of airway physiology and function during the active and resolution phases of exacerbation. o Assessment of lung structure, function and pulmonary immune responsiveness between exacerbations and the relationship between these parameters and future exacerbation frequency and severity. o Characterization of experimental interventional models (e.g. immunization, vaccination) for the protection of exacerbations. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is April 1, 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see This program does not require cost sharing as defined in the current NIH Grants Policy Statement at FUNDS AVAILABLE The NHLBI and the NIAID intend to commit approximately $5.7 million in FY 04 to fund 8 to 12 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs of up to $350,000 per year. Since the total costs for a subcontract or consortium are included in the direct cost request, one additional module of $25,000 above the cap may be requested for the facilities and administrative costs associated with third party agreements. A module requested for this purpose must be clearly identified in the budget justification section of the application, and will be restricted for this purpose only at the time of award. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI and NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. 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 institutions/organizations o Faith-based or community-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 The intent of this program is to fund clinical and basic research related to the pathobiology of asthma exacerbations. Research involving human subjects is strongly encouraged. Programs that combine basic and clinical studies are desired. Studies that confine themselves to basic research must be able to relate proposed research directly to the questions posed above, in a relevant model. Intervention-based clinical trials and long-term epidemiology studies and studies focusing on exacerbation triggers are not appropriate for this RFA. Applicants are expected to include sufficient travel funds for one RFA meeting per year to be held in Bethesda, MD. At these meetings, Principal Investigators are expected to share data and ideas with other participants in order to facilitate sharing of knowledge and collaboration in this specific area. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to 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: Patricia Noel, Ph.D. Division of Lung Diseases National Heart, Lung and Blood Institute Rockledge II, Room 10222 Bethesda, MD 20892 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: Or Hector Ortega, M.D., Sc.D. Division of Lung Diseases National Heart, Lung and Blood Institue, Rockledge II, Room 10218 Bethesda, MD 20892 Telephone: (301) 435-0202 FAX: 301-480-3557 Email: Or Ken Adams, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Room3103, MSC-6601 6610 Rockledge Drive Bethesda, MD 20892-6601 Telephone: (301) 496-8973 FAX: (301) 402-0175 Email: o Direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7214, MSC 7924 Bethesda, MD 20892-7924 Bethesda, MD 20817 (for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 o Direct your questions about financial or grants management matters to: Mr. Ephraim Johnson Grants Management Specialist Grants Operation Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7150 Bethesda, MD 20892-7926 Phone: (301) 594-9529 FAX: (301) 480-3310 Email: Or Ken Adams, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Room3103, MSC-6601 6610 Rockledge Drive Bethesda, MD 20892-6601 Telephone: (301) 496-8973 FAX: (301) 402-0175 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document to Dr. Anne Clark at the address listed under the WHERE TO SEND INQUIRES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SUPPLEMENTARY INSTRUCTIONS: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 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. For this announcement the modular ceiling has been increased to $350,000 direct costs. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at USING THE RFA LABEL: 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: 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 and all copies of the appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRES. APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or nonresponsive applications will not be reviewed. Not appropriate; budget limits, unusual use of modular.Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o 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 and assigned a priority score o Receive a written critique o Receive a second level review by the NHLBI or the NIAID 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: May 18, 2004 Application Receipt Date: June 18, 2004 Peer Review Date: October 2004 Council Review: February 10, 2005 Earliest Anticipated Start Date: April 1, 2005 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. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. DATA AND SAFETY MONITORING PLAN: (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 "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 (; a complete copy of the updated Guidelines are available at 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: The NIH maintains a policy 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 is available at 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 HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, 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 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information , the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

NIH Office of Extramural Research Logo
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy
NIH... Turning Discovery Into Health®

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.