PROGRESSION OF CARDIOVASCULAR DISEASE IN TYPE 1 DIABETES RELEASE DATE: December 4, 2003 RFA Number: RFA-HL-04-013 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: 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) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.837, 93.847 LETTER OF INTENT RECEIPT DATE: February 24, 2004 APPLICATION RECEIPT DATE: March 24, 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 The National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) invite investigator initiated applications for basic and clinical studies to enhance our understanding of the onset and progression of cardiovascular disease (CVD) in patients with type 1 diabetes. Classic CVD risk factors such as hyperglycemia, hypertension, dyslipidemia, and central obesity increase the risk of CVD in patients with type 1 diabetes, but do not fully explain the significantly higher incidence of CVD in type 1 diabetes. Thus type 1 diabetes may lead to unique mechanisms for the onset and progression of CVD, as well as influencing mechanisms known for type 2 diabetes and the general population. Identification of the mechanisms that trigger early development of atherosclerosis in type 1 diabetes is important for development of interventions to prevent and treat CVD in this population. This Request for Applications (RFA) seeks basic and clinical studies that will enhance our understanding of the effects of type 1 diabetes and its metabolic complications on the early development and fast progression of cardiovascular disease in these patients. RESEARCH OBJECTIVES Background Prevention and treatment of micro-and macro-vascular complications remain critical problems in the management of patients with diabetes mellitus. Patients with type 1 diabetes have a 4-9 fold increased risk in developing cardiovascular disease (CVD) and 75% will die from CVD, the leading cause of mortality in these patients. Type 1 diabetes constitutes 5-10% of diabetes in the United States and affects an estimated 1 million individuals. Endothelial dysfunction and accelerated atherosclerosis occur at an early age and progress at a faster rate in people with type 1 diabetes. Type 1 diabetes, unlike type 2, is characterized by autoimmune destruction of pancreatic beta cells, leading to an inability of the pancreas to make insulin. Daily administration of exogenous insulin is essential for life, but current therapeutic regimens do not replicate normal glucose homeostasis and are associated with substantial short and long term complications. Endothelial dysfunction is a condition in which the vascular endothelium undergoes changes in the expression of molecules, such as endothelin, FGF, angiotensin II, PGDF, VCAM, adhesion molecules, and others. Also, blunting of the nitric oxide-dependent vasodilatory responses can occur. Endothelial dysfunction has been documented in patients with both type 1 and type 2 diabetes, as well as in individuals at high risk for cardiovascular disease. Studies on the mechanisms and agents that trigger endothelial dysfunction in patients with type 1 diabetes are needed to elucidate the relevant role of endothelial dysfunction in the development of atherosclerosis in the type 1 population. It is now accepted that inflammation plays a key role in cardiovascular disease. Inflammatory factors, such as cytokines and adhesion molecules, have been shown to be involved in the development and propagation of the atherosclerotic lesion. In animal models of obesity it has been suggested that specific mediators of proinflamatory responses may contribute to insulin resistance. Although specific mechanisms have not been elucidated, obese humans and patients with type 2 diabetes have elevated levels of TNF alpha, IL-6 and C-Reactive Protein (CRP). CD40 ligand, a proinflamatory and atherogenic cytokine, and CRP were also reported to be elevated in type 1 diabetic patients. Thus, the autoimmune etiology of type 1 diabetes and the potential role of inflammation in the development of atherosclerosis, point to inflammation and the immune system as target areas for more investigation. Controlling high blood glucose levels is beneficial in reducing or delaying the development of microvascular complications in type 1 diabetes, but its effect on macrovascular complications is not as clear. Recent findings from the long term follow-up of participants in the Diabetes Control and Complications Trial (DCCT) demonstrated decreased incidence of atherosclerosis, assessed in carotid ultrasound and coronary computerized tomography, in the study participants who intensively controlled blood glucose. The difference between the intensive and conventional treatment groups became manifest well beyond the 6.5 year clinical trial; the reduction in atherosclerosis was seen in the follow-up study in which glucose control was similar in the two groups. Of note, recent findings from the follow-up study also demonstrate persistent reduction in the risk of microvascular complications continue 7-8 years after the completion of the study, even in the presence of similar glycemic levels. Studies on the mechanism of CVD in type 1 diabetes may have to consider the possible metabolic memory effect, whereby a history of elevated glucose levels leads to enduring effects on the vasculature. Recent data in vitro have implicated hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. Overproduction of superoxides by the mitochondrial electron-transport chain seems to activate pathways that have been suggested to be involved in the vascular complications caused by hyperglycemia. Despite the evidence of the role of oxidative stress in the development of cardiovascular complications in patients with diabetes clinical trials using antioxidants have failed to demonstrate any beneficial effect. Thus, research is needed to translate the basic science findings on oxidative stress into improved outcomes. Recent studies suggest that factors related to insulin resistance might predict coronary artery disease in patients with type 1 diabetes. Insulin resistance is a condition in which peripheral tissues like skeletal muscle and adipose tissue are inefficient or unable to utilize glucose for tissue specific processes like protein synthesis or lipogenesis, respectively. As a result, there is an increase in insulin levels and requirements and an elevation in fasting and postprandial glucose and lipid levels in the circulation. Insulin resistance has been associated with the development of atherosclerosis and is a major risk factor for heart disease in patients with type 2 diabetes. Patients with type 1 diabetes are not immune to insulin resistance and the development of double diabetes . Intensive insulin therapy may even increase the development of obesity and insulin resistance. For patients with type 2 diabetes, insulin resistance is associated with endothelial dysfunction, but little is known about the impact of insulin resistance on the vasculature of patients with type 1 diabetes, and its contribution to alterations in vascular permeability and acceleration of cardiovascular disease. Receptors for advanced glycation end products (RAGE) play a role in the atherogenic process in diabetic animal models, likely by mediating inflammation and activation of vascular adhesion molecules. Blockade of RAGE stabilizes the atherosclerotic plaque and delays atherogenesis in mice. Besides AGEs, several ligands for RAGE have been identified, such as the S100/calgranulins which are members of a family of proinflamatory cytokines. An increased expression of RAGE and its ligands occurs under diabetic conditions and suggests the important role of these receptors in diabetic vasculopathies. Due to its great potential as a therapeutical target, more research is needed to better understand the physiological and pathological role of these receptors as well as the mechanisms involved in receptor activation. Similarly, another family of receptors, the nuclear receptor peroxisome proliferator-activated receptor (PPAR) has been shown to be of great importance for treatment of type 2 diabetes. PPAR gamma agonists reduce circulating levels of free fatty acids, increase glucose metabolism, increase insulin sensitivity as well as to have actions in the vasculature through anti-inflammatory effects. However, PPARs are also proatherogenic by promoting foam cell formation and acting on cell types that are involved in atherogenic processes. Research is needed to elucidate the role of PPARs and other nuclear receptors in the initiation and progression of atherosclerosis in type 1 diabetes. The abnormal lipid profile observed in type 1 diabetic patients is believed to be largely a consequence of the dysregulation of lipid metabolism. Nuclear magnetic resonance spectroscopy has shown differences in lipoprotein particle size. Human aortic endothelial cells incubated with LDL from type 1 diabetic patients showed an increase in the activity of several endothelial-related cellular mechanisms. In a recent study, increased intraabdominal fat was directly correlated to increased hepatic lipase activity in subjects with type 1 diabetes. Given the significance of dyslipidemia in the overall development of CVD, the role of lipids and lipid metabolic pathways in type 1 diabetes needs further investigation. Cardiovascular complications of type 1 diabetes often accompany signs of nephropathy. Indeed, both microalbuminuria and depression in glomerular filtration are epidemiologically linked to cardiovascular events. This connection may reflect parallel accrual of macrovascular and microvascular injury with the renal damage being more accessible to clinical measurement. However, the kidney damage may also engender nontraditional risk factors for macrovascular injury. For example, accumulation of homocysteine, disturbances in calcium-phosphorous metabolism and renal hypertension may accelerate cardiovascular injury. Understandings the nexus of diabetic nephropathy and cardiovascular disease requires further study. For patients with type 2 diabetes, progress has been made in elucidating mechanisms for their accelerated onset of CVD. Some but not all of these mechanisms are likely to be relevant for CVD in type 1 diabetes. Identification of common or unique pathways between the two types of diabetes mellitus will advance our understanding of type 1 diabetes research considerably and offer new tools for the development of new therapies and tailored interventions. Objectives and Scope The causes of the increased incidence and earlier onset of cardiovascular disease in patients with type 1 diabetes are still unknown. The question remains whether the importance of the known risk factors for CVD in type 2 diabetes, like inflammation, endothelial dysfunction and dyslipidemia, also applies to type 1 diabetes or whether other factors of unknown etiology are responsible for the enhanced cardiovascular complications in this group. Fostering research with a focus on the vascular wall and endothelia dysfunction in the setting of type 1 diabetes will increase our knowledge of the factors that contribute to the development of cardiovascular disease in these patients. Understanding the mechanisms involved will provide the necessary information to develop a better rationale for prevention and treatment programs tailored to individuals with type 1 diabetes. The objective of this initiative is to investigate and elucidate the elements and mechanisms involved in the development of accelerated cardiovascular disease in type 1 diabetes. These studies may range from basic studies on the mechanism of CVD in type 1 diabetes to clinical studies that would use new analyses of existing datasets or collection of additional data and biological specimens in ongoing investigations. Appropriate topics for investigation under this RFA would include, but are not limited to: o Evaluate the role of inflammation and immune factors in the onset and progression of atherosclerosis, plaque stability, endothelial dysfunction, and vascular changes leading to cardiovascular disease in type 1 diabetes. o Evaluate the role of hyperglycemia and insulin resistance on the onset and progression of atherosclerosis, on plaque stability, and in precipitating pathologic changes in endothelial function and vascular permeability in type 1 diabetes. o Elucidate the role of receptors, such as RAGE and nuclear receptors, in type 1 diabetic cardiovascular complications. o Investigate vascular lipid metabolism and its regulation by factors such as hyperglycemia, inflammation and insulin resistance and their contribution to cardiovascular complications of type 1 diabetes. o Examine the mechanisms whereby nephropathy in type 1 diabetes is linked to and may accelerate cardiovascular disease. o Investigate the mechanisms of cardiovascular complications in existing cohorts of type 1 diabetes by utilizing stored samples or data collections. For these studies, both government and non-government supported clinical trials and epidemiologic studies are eligible. Analysis of large public access databases and other databases is also encouraged. MECHANISM OF SUPPORT This RFA will use NIH R01 (investigator-initiated research project grant) 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 September 30, 2004. 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 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 budget format. Otherwise follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. Applications submitted by foreign institutions can request facilities and administrative (F&A) costs up to a maximum of eight percent. Please see the web site HTTP://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html for more information on allowable F&A costs for foreign grants and domestic grants with foreign components. FUNDS AVAILABLE The participating ICs intend to commit up to a total of $3,000,000 in FY 2004 to fund 6 to 8 new 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 $400,000 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 ICs 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 Grantee's Meetings Upon initiation of the program, the NHLBI and the 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 in about 6 months after the award is issued. Restrictions and Exclusions This RFA is intended to support multidisciplinary R01 research programs studying the complications of cardiovascular disease in type 1 diabetes and must propose mechanistic studies. To be responsive to this RFA, the studies must be unequivocally and directly relevant to type 1 diabetes and not to other forms of diabetes. Applications that propose new large epidemiological studies or large clinical trials will be considered unresponsive to this initiative. Ancillary studies to completed or ongoing clinical studies are within the scope of the initiative. 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: Cristina Rabadan-Diehl, Ph.D. Division of Heart and Vascular Diseases National Heart,Lung, and Blood Institute 6701 Rockledge Drive Rockledge II, Room 10186 Bethesda, MD 20892-7164 Telephone: (301) 435-0550 FAX: (301) 480-2858 Email: rabadanc@nhlbi.nih.gov Teresa L. Z. Jones, MD Program Director for Diabetes Complications DEM/NIDDK/NIH 6707 Democracy Blvd. Room 651 Bethesda, MD 20892-5460 Telephone: (301) 435-2996 FAX: (301) 480-3503 Email: jonest@extra.niddk.nih.gov o Direct your questions about peer review issues to: Anne 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 Email: ClarkA@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Susan Lowenthal Grants Management Specialist NHLBI 6701 Rockledge Drive Rockledge II, Room 7155 Bethesda, MD 20817 Telephone: (301) 435-0159 FAX: (301) 480-3310 Email: lowenths@nhlbi.nih.gov Kathleen J. Shino, MBA Supervisory Grants Management Specialist NIDDK 6707 Democracy Blvd., Room 708 Bethesda, MD 20892-5456 Telephone: (301) 594-8869 FAX: (301) 594-9523 Email: shinok@extra.niddk.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 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. The letter of intent should be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. 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 http://www.dunandbradstreet.com/. 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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, 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/labels.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 and all copies of the appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. 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. 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 National Advisory Council 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? 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. 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: February 24, 2004 Application Receipt Date: March 24, 2004 Peer Review Date: June/July 2004 Council Review: September 2004 Earliest Anticipated Start Date: September 30, 2004 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. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 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 (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://stemcells.nih.gov/index.asp 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, 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 (http://www.hhs.gov/ocr/) 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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. 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.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ 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 http://grants.nih.gov/grants/policy/policy.htm. 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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