PATHOPHYSIOLOGIC MECHANISMS OF OBESITY-ASSOCIATED CARDIOVASCULAR DISEASE RELEASE DATE: January 25, 2002 RFA: RFA-HL-02-016 PARTICIPATING INSTITUTES AND CENTERS (ICs): National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (http://www.niddk.nih.gov) LETTER OF INTENT RECEIPT DATE: May 20, 2002 APPLICATION RECEIPT DATE: June 19, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The purpose of this Request for Applications (RFA) is to stimulate novel research approaches to clarify the biologic basis of various obesity- related cardiovascular diseases and disorders, including atherosclerosis, thrombosis, hypertension, cardiomyopathies, heart failure, and arrhythmias/sudden death. Emphasis will be placed on basic and clinical mechanistic research that reflects expertise in both obesity and cardiovascular sciences. Areas of high interest in association with cardiovascular disorders include: adipose tissue as a pro-inflammatory and pro-thrombotic endocrine organ; lipid infiltration (lipotoxicity) in non-adipose tissues and organs; maladaptation of the cardiovascular, endocrine, and neural systems in obesity; and the impact of obesity on the maturation of the cardiovascular system in young animals. Applications may also include the development of shared research resources, provided these are proposed in conjunction with hypothesis-testing study designs. RESEARCH OBJECTIVES Background The adult United States population, whose combined prevalence of overweight and obesity now exceeds 60 percent, is experiencing a mass exposure to obesity-related cardiovascular risk factors and will likely suffer the adverse clinical consequences in years to come. Overweight or obese individuals experience greatly elevated morbidity and mortality from nearly all of the common cardiovascular diseases (stroke; coronary heart disease; congestive heart failure; cardiomyopathy; and possibly arrhythmia/sudden death). This is partly attributable to co-morbidities and risk factors such as type 2 diabetes, insulin resistance, hypertension, and dyslipidemias. The residual independent effects of obesity on cardiovascular risk, however, detected in long-term prospective studies with decades of observation, suggest a role for less well-characterized mediators such as sleep-disordered breathing, autonomic dysregulation, and pro-thrombotic and pro-inflammatory states. Also alarming are the ever rising rates of overweight and obesity in children and adolescents, which have tripled over the last 30 years. Increased rates of co-morbidities such as type 2 diabetes and hepatic damage in overweight adolescents indicate that the young are not protected from the metabolic perturbations that accompany excess adipose tissue stores. We do not know what the consequences might be for the still-developing cardiovascular system if obesity is present during late stages of growth and maturation. The specific relationships between obesity and cardiovascular risk vary considerably with gender, race, and type of heart disease. For example, congestive heart failure risk is similarly elevated in overweight/obese males and females. There is debate, however, regarding whether there are gender differences in risk of coronary heart disease at given degrees of overweight. The effect of adiposity on stroke risk, on the other hand, appears to vary with race as well as gender. These varied findings suggest that complex underlying phenomena may mediate the relationship between excess adipose tissue and elevated cardiovascular disease risk. For example, the biological implications of gender- and race-related differences in adipose tissue distribution should be explored. Also, differences in hormone metabolism and hormonal effects on cardiovascular biology, including the role of androgens, estrogens, and hormone-replacement therapies, need further study. Mechanistic Studies in Animals and Humans Because primary treatment and prevention of obesity often fail or are only partially successful, it is anticipated that the future will bring ever-increasing demands to treat the cardiovascular conditions attributable to obesity. Thus, in order to develop rational therapeutic approaches, we need to understand the basic biology of obesity-related cardiovascular disease. Adipose tissue as a metabolically active endocrine organ: While a major role of adipose tissue is the storage of lipid energy, recent work has highlighted the role of adipose tissue as a metabolically active endocrine organ. Notably, insights into the biology of the secretion of the hormone leptin from adipocytes and its action in the central nervous system have contributed to our understanding of the regulation of energy balance. However, leptin=s direct effects on the cardiovascular system are only now being revealed. For example, important interactions between adipose tissue and coagulation pathways have been suggested by recent reports that platelet membranes contain leptin receptors. Studies also are needed to clarify leptin=s effects on sympathetic nervous activity and cardiovascular functions such as blood pressure control. Likewise, more research is needed regarding the intriguing connections between leptin physiology and sleep physiology suggested by observations that repeated interruptions in breathing due to sleep apnea may lead to altered plasma leptin levels. Other newly discovered molecules of adipose tissue origin, such as perilipin, adiponectin, and resistin, are potentially of interest with regard to their interactions with the cardivascular system. Adipocyte- derived angiotensinogen and angiotensin II are of interest because the renin/angiotensin/aldosterone system plays a major role in the pathophysiology of hypertension and related sequelae such as cardiac hypertrophy, diastolic dysfunction and heart failure. The importance of specific metabolic characteristics of various regional fat depots has recently been underscored by observations that abdominal obesity is associated with the upregulation of 11-beta-hydroxysteroid dehydrogenase type 1 in visceral fat. This may have implications for the relationship between this type of obesity and development of the metabolic syndrome (Syndrome X). Lipotoxicity in muscle and other non-adipose tissues: The deleterious effects of increased infiltration of free fatty acids (FFA) into various organs and tissues have been collectively termed "lipotoxicity". The potential importance of this concept was recently highlighted by animal studies suggesting that excess fatty acids help destroy cardiac myocytes by increasing triglyceride content and the rate of apoptosis. Lipid accumulation in the pancreas and the liver also conveys serious functional risks. Still unclear are the mechanisms for the tissue-specific uptake of FFA and their deposition into stored lipid pools; the molecular and pathophysiologic basis for the organ-specific toxicity of lipid accumulation; and the relationship of such lipid deposition to development of various cardiovascular diseases. We also need to understand the ways in which the functional effects of lipotoxicity in the heart and vascular tissues are distinct from those of glucotoxicity. In addition, more research is needed on the basic mechanisms of human lipotoxic heart disease and obesity cardiomyopathy. Inflammation and thrombosis: It is now well accepted that inflammation is a major component of atherosclerosis. Moreover, adipose tissue is now recognized as a source of inflammatory mediators, with production of cytokines such as TNF- alpha and interleukin-6. It appears likely, but is far from proven, that the relationship between obesity, insulin resistance, and atherosclerosis may depend at least in part on the increased production and release of these inflammatory mediators from adipose tissue. Other secretory products of adipose tissue (e.g. angiotensin II) and their relationship to inflammation in obesity also need to be investigated. Obesity is a pro-thrombotic state, possibly as a secondary effect of insulin resistance; this is a contributing factor to elevated risk of coronary heart disease and stroke. Pulmonary thromboembolic disease also occurs at higher rates in the obese, in part but perhaps not entirely due to venous stasis. For example, the increased flux of FFA that occurs in obesity likely promotes thrombosis through alterations in protein C, tissue factor PAI-1 and/or enhanced platelet aggregation. Enhanced secretion of inflammatory mediators from an expanded adipose tissue compartment may also activate thrombotic mechanisms in obesity. Hemodynamic and neural/sympathetic regulation: Many hemodynamic abnormalities have been described in obesity, including elevated cardiac output, altered vascular reactivity, hypertension, diastolic dysfunction, and cardiomyopathy. It is not clear whether these abnormalities stem from direct effects of adipose tissue excess, in addition to well-known secondary or indirect mechanisms. For example, the hemodynamic pathophysiology in obesity apparently derives in part from maladaptive neural regulation of the circulation in the setting of an expanded adipose tissue mass. Also, the obstructive sleep apnea that frequently occurs in obesity produces abrupt increases in sympathetic activity, with altered vascular responses that include increased blood pressure, all of which persist even through the waking hours; obstructive sleep apnea thus may be an important secondary cause of hypertension. Both the central and peripheral nervous systems appear to be intricately involved in the development of obesity and also in the resulting cardiovascular complications. Sympathetic activation is involved in many of the cardiovascular complications of obesity, including hypertension, diastolic dysfunction, congestive heart failure, obstructive sleep apnea, and cardiac arrhythmias. The mechanisms for this dysregulation and complex, integrated afferent and efferent signals are poorly understood. In addition, altered renal function and excess sodium reabsorption by the kidney play a major role in obesity-induced hemodynamic abnormalities. In experimental animals, caloric excess causes renal disease as well as obesity, whereas caloric restriction protects against injury to the glomerulus. However, the mechanisms that link obesity with impaired kidney function are poorly understood. For example, the mechanisms that cause progressive nephron loss are unclear. Few clinical or experimental studies have examined the initial changes in glomerular structure and function in the early stages of obesity. These changes may be the precursors to the development of more severe glomerulosclerosis and eventual loss of nephron function, and also be markers for more generalized vascular disease. The factors that allow risk stratification and those that predict pharmacological responsiveness to drugs such as angiotensin converting enzyme inhibitors and aldosterone antagonists also need to be understood. Lipid metabolism, hyperinsulinemia, and atherosclerosis: The relative roles of various lipid and lipoprotein disturbances in subsequent development of coronary heart disease in obesity are still not fully understood. The most common lipid disturbance in obese patients is the reduction of plasma high density lipoprotein (HDL) cholesterol concentration. This abnormality in part derives from compositional changes in HDL that reflect the hypertriglyceridemic state (i.e., replacement of cholesteryl ester by triglycerides), but reduced HDL cholesterol levels are often seen in obese patients without increases in serum triglycerides. A more in-depth understanding of the origin of low levels of HDL in obesity is ripe for basic and translational study. Increased progression of atherosclerosis in obesity may also be related to increased levels of apoB lipoproteins. Increased secretion of VLDL- apoB has been related to increased free fatty acid flux, causing decreased intracellular degradation and hence increased secretion. A few studies have suggested that insulin resistance at the level of the hepatocyte can also lead to increased apoB secretion. The mechanisms linking free fatty acid flux or insulin resistance (at the level of the hepatocytes) to increased apoB secretion are incompletely understood and deserve further study. Insulin resistance, apparently a primary mechanism of type 2 diabetes, has received little attention as a mechanism of increased atherosclerosis risk. Changes related to hyperglycemia or defective insulin signaling may also be involved in the increased atherosclerosis risk associated with obesity. For example, in diabetic humans blood glucose control is not well correlated with atherosclerotic cardiovascular disease, in contrast to the beneficial effects on microvascular disease. Also, in murine models hyperglycemia has not been clearly shown to increase atherosclerosis, independent of plasma lipid changes. Furthermore, the possibility that obesity-related defects in insulin signaling affect the behavior of cells in the atherosclerosis-susceptible regions of arteries warrants investigation. A very small number of studies suggest there may be pro-atherogenic abnormalities of endothelial cells or macrophages that could be related to defects in insulin signaling. Furthermore, the mechanism by which the hyperinsulinemia of obesity contributes to cardiovascular disease is not well understood, and may not be simply explained by an association between insulin resistance and coexisting factors such as dyslipidemia. For example, there are recent data that indicate the metabolic effects of insulin action are biochemically distinct from the mitogenic effects of the hormone. Moreover, some models demonstrate that when insulin resistance is present in the metabolic pathways of insulin action, the mitogenic pathways are not only maintained, but in fact show compensatory increases. This could promote atherogenic events in the arterial wall. Research Resources In conjunction with proposed hypothesis-testing research designs, applications may also include usage and/or development of various types of research resources, which could range from whole animals to immortalized cell lines to advanced instrumentation. Applicants are encouraged to describe plans for sharing such resources with other investigators. Animal models: To examine the cardiovascular pathophysiology of obesity, consideration should be given to novel uses of currently available genetic and experimental models. Nevertheless, suitable animal models for examining the impact of obesity on cardiovascular disease are relatively limited at present, and new ones need to be developed. For example, large animal models (e.g., non-human primates, swine) may be appropriate for certain investigations. Also, immature and growing animals could be studied at various stages of the life cycle. Furthermore, in addition to diet-induced and genetically-based animal models of obesity and overweight, distinct lean and thin phenotypes may be useful. Technology: Applicants are encouraged to propose research that takes advantage of, and further builds upon, recent technology developments. Complex instrumentation for phenotyping could be considered as appropriate. Examples include ultrasound, computerized tomography, and magnetic resonance imaging techniques to enhance the definition of body and organ composition and whole room or chamber calorimeters to assess animal and human energy balance. Mass spectrometric analysis of stable isotope turnover may be useful in identifying mechanisms for tissue-specific fuel utilization. The development of methods for high-throughput macromolecular identification of tissues and cells and non-invasive methods of assessing lipid infiltration into tissues and organs would be useful. DNA and protein microarray analyses could be applied to the investigation of tissues from various body compositional phenotypes of animals and humans. Summary of Priority Areas Areas of particularly high interest for mechanistic research in humans and animals include: o Adipose tissue as a pro-inflammatory, pro-thrombotic endocrine organ affecting the cardiovascular system o Lipid infiltration as a cause of target organ injury in the cardiovascular system o CNS adaptation and autonomic activation in obesity, including sleep apnea, and their impact on cardiovascular regulation o Obesity-associated hypertension and hypertensive renal disease o Cardiovascular adaptations to obesity during various stages of development and maturation, from childhood through adolescence o Hyperinsulinemia, insulin resistance, and other endocrine dysregulation syndromes of obesity as related to cardiovascular disease MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Individual Research Project Grant (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, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE The NHLBI intends to commit approximately $6,000,000 (Total Cost) and the NIDDK intends to commit approximately $1,000,000 (Total Cost) in FY2003 to fund approximately 10-12 new grants in response to this RFA. An applicant may request a project period not to exceed 5 years and a budget for direct costs not to exceed $500,000 per year. 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 NIDDK 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 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 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 his or her institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Exclusions Certain types of investigations, although potentially of scientific interest, will not be appropriate for support by this program. Applications proposing non-mechanistic, non-hypothesis-based research will be considered non-responsive to the RFA. Examples of excluded studies are: prospective or descriptive epidemiology studies (e.g., investigating health risks of obesity); clinical trials whose primary purpose is to test effectiveness of treatments or interventions for obesity or associated cardiovascular diseases; studies having a primary focus on causation of obesity or on mechanisms of energy balance; studies having a primary focus on cardiovascular conditions, but which do not include the biology of obesity or overweight as an aspect of the experimental design; and projects having a primary focus on research resource development. Grantees= Meetings Upon initiation of the program, the NHLBI and NIDDK will sponsor annual meetings to encourage exchange of information among investigators who participate in this program. In their budgets, applicants should include funds for annual one-day grantees= meetings, most likely in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. The first such meeting likely will take place within 3 months of award. General Clinical Research Center (GCRC) Applicants from institutions that have a 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. Additional Considerations All grant applications submitted in response to this RFA should include sample size and statistical power calculations appropriate to the proposed study design. In addition, applicants proposing development of research resources are encouraged to describe a plan to share such resources with other researchers. This could include appropriate information technology (such as DNA/protein microarray databases) or shipment of animals or tissues. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. It is particularly recommended that prospective applicants make these inquiries, especially regarding scientific/research issues, as soon as possible, i.e., considerably in advance of submitting the Letter of Intent. Doing so will allow a preliminary evaluation of responsiveness to be made at an early stage and will help to prevent the preparation and/or submission of an unresponsive application. 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: Abby G. Ershow, Sc.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive Suite 10193, MSC 7956 Bethesda, MD 20892-7956 Telephone: (301) 435-0550 or 435-0526 Fax: (301) 480-2858 Email: ErshowA@nhlbi.nih.gov Carl E. Hunt, M.D. Director, National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute 6701 Rockledge Drive Suite 10038 MSC 7920 Bethesda, MD 20892-7920 Telephone: (301) 435-0199 Fax: (301) 480-3451 Email: HuntC@nhlbi.nih.gov Susan Z. Yanovski, M.D. Director, Obesity and Eating Disorders Program Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, MSC 5450 Bethesda, MD 20892-5450 Telephone: (301) 594-8882 Fax: (301) 480-8300 Email: sy29f@nih.gov o Direct your questions about peer review issues, letters of intent, and application procedures to: Anne Clark, Ph.D. Chief, Review Branch 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) 480-0730 Email: ClarkA@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: David Reiter Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive Suite 7159, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0153 FAX: (301) 480-3310 Email: ReiterD@nhlbi.nih.gov 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 NHLBI staff to estimate the potential review workload and plan the review. Such letters also are helpful to staff in making a preliminary assessment of responsiveness to the RFA. The letter of intent is to be sent by May 20, 2002 to: Anne Clark, Ph.D. Chief, Review Branch 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) 480-0730 Email: ClarkA@nhlbi.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. 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: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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 as well as all five collated sets of Appendix material must be sent to: Anne Clark, Ph.D. Chief, Review Branch 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) 480-0730 Email: ClarkA@nhlbi.nih.gov Please note that applications delivered by individuals are no longer accepted; all applications must either come via courier delivery or the USPS (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html). APPLICATION PROCESSING: 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. 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. Anne Clark at the address listed under Inquiries. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. 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. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by the NHLBI and NIDDK National Advisory Councils. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application=s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA AND RESOURCE SHARING: The adequacy of the proposed plan to share data and/or resources, as appropriate for the scientific goals of the research. o 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 20, 2002 Application Receipt Date: June 19, 2002 Peer Review Date (estimated): October/November, 2002 Council Review: February 6-7, 2003 Earliest Anticipated Start Date: April 1, 2003 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 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 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: 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 http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.837 (for DHVD/NHLBI), and No. 93.848 (for DDDN/NIDDK) and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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