EXPIRED
Collaborative Studies on Angiogenesis and Diabetic Complications
Request For Applications (RFA) Number: RFA-DK-04-022 (see addendum, NOT-DK-05-003)
Department of Health and Human Services
Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov/)
Components of Participating Organizations
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),
(http://www.niddk.nih.gov)
National Institute of Neurological Disorders and Stroke (NINDS),
(http://www.ninds.nih.gov)
National Heart, Lung, and Blood Institute (NHLBI),
(http://www.nhlbi.nih.gov)
National Eye Institute (NEI),
(http://www.nei.nih.gov/)
Announcement Type
New
Catalog of Federal Domestic Assistance Number(s)
93.847, 93.853, 93.867 and 93.837
Key Dates
Release Date: November 3, 2004
Letters of Intent Receipt Date(s): February 17, 2005
Application Receipt Date(s): March 17, 2005
Peer Review Date(s): June-July, 2005
Council Review Date(s) : September 14-15, 2005
Earliest Anticipated Start Date: September 30, 2005
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: March 18, 2005
Due Dates for E.O. 12372
Not Applicable
Additional Overview Content
Executive Summary
Table of Contents
Part I Overview Information
Part II Full Text of Announcement
Section I. Funding Opportunity Description
1. Research Objectives
Section II. Award Information
1. Mechanism of Support
2. Funds Available
Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing
3. Other - Special Eligibility Criteria
Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements
Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Merit Review Criteria
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
Section VI. Award Administration Information
1. Award Notices
2. Administrative Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilites
4. Arbitration Process
3. Award Criteria
4. Reporting
Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)
Section VIII. Other Information - Required Federal Citations
Part II - Full Text of Announcement
Section I. Funding Opportunity Description
The significant morbidity and mortality of Type 1 diabetes mellitus result predominantly from its complications, including blindness, renal failure, amputations, strokes and heart attacks. Hyperglycemia is the metabolic hallmark of diabetes and leads to widespread cellular damage. Endothelial cells, which poorly regulate intracellular glucose, may be particularly vulnerable to hyperglycemia. An excess of glucose sets off a chain of metabolic events that culminate in overproduction of reactive oxygen species in the mitochondria and which in turn leads to increased flux in the hexosamine and polyol pathways, increased formation of advanced glycation endproducts and activation of protein kinase C. These metabolic changes result in a plethora of tissue-specific functional defects with diabetes-associated vasculopathy as the central mediator of the pathophysiology of diabetic complications.
The growth of new blood vessels from existing ones (angiogenesis) is a complex process involving a number of specific vascular growth factors, cell types and extracellular matrix proteins. Under appropriate physiologic and pathophysiologic conditions, growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are released to initiate angiogenesis. Through a complex signal transduction pathway, endothelial cells divide or precursors of these cells migrate to the site of new blood vessel formation to form the nascent endothelial tube. Support cells such as pericytes and smooth muscle cells derived from mesenchymal cells overlay the endothelial tube and contribute to vessel remodeling and the arterialization of the vessel.
Studies suggest that the metabolic abnormalities of diabetes alter the angiogenic process. There are several mechanisms by which, angiogenesis may be vulnerable to the metabolic abnormalities of diabetes, though the extent and nature of this vulnerability is poorly understood. Non-enzymatic glycation that leads to advanced glycation end-products in serum and tissues can inhibit extracellular matrix (ECM) degradation, leading to both a decrease in the release of angiogenic factors from the ECM and an expansion of ECM and hypoxia-induced neovascularization. Hyperglycemia has been associated with altered expression of growth factors (VEGF, FGF, angiogenin and 12-HETE) and ECM proteins (fibronectin). Diabetes is also associated with a chronic inflammatory state that damages micro- and macrovessels, and may well impede the growth of new vessels.
The metabolic defects of diabetes may be wide-ranging, but the clinical trial and epidemiologic data demonstrate that hyperglycemia per se is central to the vascular complications of Type 1 diabetes. This is an advantage for developing therapies as compared to other conditions such as cancer in which mutagenesis is an ongoing process that creates unique tumor phenotypes. Therapies to inhibit or stimulate angiogenesis that are being developed for other conditions may be highly efficacious for diabetic complications.
Diabetic retinopathy and neural manifestations
Abnormal angiogenesis in diabetes is most clinically apparent in proliferative diabetic retinopathy. The neovascularization is preceded by the selective destruction of pericytes, capillary failure and hypoxia that leads to the release of proangiogenic substances. The resulting vessels have increased permeability and are prone to rupture. Macular edema is another form of retinopathy in which increased permeability of blood vessels leads to deposition of extracellular protein. Therefore, the goal of effective therapy for diabetic retinopathy is not only to decrease the excess vessel growth, but also to restore normal vessel permeability and blood flow to the retina.
The effects of diabetes on angiogenesis in neural tissues other than the retina have not been well-studied. It is known that angiogenic remodeling occurs in the central nervous system in response to stimuli such as exercise or traumatic and ischemic injury. It is also known that diabetes has deleterious effects on the peripheral and central vasculature, as well as on neurons themselves. For example, there is increased risk of stroke and other types of cerebrovascular accidents in diabetes. Hence, an important future area of inquiry will be to determine whether these diabetic complications are accompanied by angiogenesis, and whether (as in the retina) the newly formed vessels are abnormal.
Diabetic wound healing
Impaired wound healing is a common condition in diabetes associated with a delay in progression beyond the inflammatory and proliferative phases of normal wound healing. Animal models of diabetes show reduced angiogenesis in healing of skin incisions. In diabetic patients, the blood vessels at the wound edge are abnormal with cuffing of collagen and other proteins, the fibroblasts have decreased proliferative capacity and an abnormal morphology and the ECM shows prolonged presence of fibronectin. Topical treatment of wounds with single growth factors have shown only minimal efficacy. A better understanding of the abnormalities in angiogenesis in diabetic wounds could lead to new targets for intervention. For example, the circulating endothelial progenitor cells (EPC), which play a critical role in forming new vessels, are dysfunctional in diabetes. Discovery of the defects in these cells and the means to correct them could lead to autologous cell therapies for diabetic wounds. The accessibility of wounds also makes them a good model system for developing biomarkers and imaging tools for angiogenesis.
Peripheral and Coronary Arterial Disease
Diabetes is one of the strongest risk factors for peripheral arterial disease (PAD). PAD can lead to severe limb ischemia where amputation is the only recourse, especially in diabetics. Although studies in non-diabetic and diabetic animals suggest that the reduced angiogenic response in limb ischemia can be reversed by vascular growth factors, clinical trials using these growth factors have proven to be far from successful in both diabetic and non-diabetic patients. It has been suggested that the responsiveness to angiogenic stimuli in PAD is impaired and conceivably more so in diabetics, suggesting that critical studies are needed to understand the uniqueness of the problem.
Collateralization (arteriogenesis) within the myocardium following an ischemic episode is believed to provide a survival benefit by limiting the zone of infarction following the occlusion of one or more coronary arteries. In individuals with diabetes, this collateral vessel development is blunted, with little known on the mechanism behind this finding. Understanding how a diabetic background alters the arteriogenic process should lead to important treatment options for coronary artery disease in diabetics.
Other complications
A role for excessive angiogenesis in the early phases of diabetic nephropathy has been suggested. Glomerular capillary surface increases early in diabetes, and studies in diabetic animals suggest that an anti-angiogenic peptide can inhibit the early lesions of diabetic nephropathy. Embryonic vasculopathy associated with maternal diabetes may be due to abnormal angiogenesis. The abundant expression of angiogenic factors in the placenta of non-diabetic women is altered in diabetic women and correlates with vascular malformations.
2. Research Topics
The objective of this RFA is to stimulate research on the abnormal angiogenesis seen with Type 1 diabetes and the mechanisms that lead to these abnormalities in order to develop therapies, biomarkers and imaging tools to improve the diagnosis and treatment of diabetic complications.
Tremendous strides have been made in understanding normal and pathologic angiogenesis and in particular for diabetes, the abnormalities in angiogenesis in diabetic retinopathy. The goal of this RFA is to extend studies of angiogenesis beyond diabetic retinopathy to other complications of diabetes, including peripheral, coronary and cerebral arterial disease, neuropathy, wound healing, nephropathy and embryopathy. Where defects in angiogenesis are well-documented, research in common underlying mechanisms of abnormal angiogenesis would be appropriate for this RFA.
Research proposals must focus on both Type 1 diabetes and angiogenesis and can use tissue culture methods, animal models and clinical studies. Clinical studies for diabetic retinopathy would not be considered responsive to this RFA. Research on the effects of diabetes on specific components of vessels (eq. endothelial cells, pericytes, ECM) would be responsive, if linked to a functional assessment of angiogenesis. Applications proposing research on the impact of diabetes on existing blood vessels would not be considered responsive to this RFA.
Applications should propose collaborative research partnerships between researchers with experience in diabetes and angiogenesis. Each research partner should be a successful independent investigator with a track record of successful research accomplishments. Each of the research partners will serve as a principal investigator on a grant application within a collaborative project. The level of effort proposed by the collaborating independent investigators should be appropriate for the scope of the project.
Appropriate topics for investigation under this RFA would include, but are not limited to:
The impact of the chronic inflammatory state produced by hyperglycemia and diabetes on angiogenesis.
The abnormalities in pericytes produced by diabetes that leads to vascular instability during angiogenesis.
The changes associated with diabetes in endothelial progenitor cells that alter their targeting to specific tissues and formation of new blood vessels.
The effects of diabetes on reducing the quality of newly formed blood vessels, especially changes in permeability.
Characterization of angiogenesis in the pathophysiology of diabetic nephropathy including any changes that occur between early and late stage disease.
Mechanistic studies in appropriate animal models focusing on the revascularization in peripheral and coronary artery disease in a diabetic background.
The effects of diabetes on angiogenesis in the central and peripheral nervous systems, including possible effects on the capacity to mount normal angiogenic responses to stimuli such as exercise and tissue injury.
Investigation of mechanisms underlying the increased risk in diabetes of stroke and other types of cerebrovascular accidents with respect to angiogenesis and arteriogenesis.
Mechanistic studies to better understand the failure of administration of a single angiogenic growth factor to significantly improve arterial disease or wound healing.
Section II. Award InformationThe anticipated start date is September 30, 2005
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 IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Fiscal and administrative costs are not included in the direct cost limitation, see NOT-OD-04-040 .
Section III. Eligibility Information
1. Eligible Applicants
1.A. Eligible Institutions
You may submit (an) application(s) if your organization has any of the following characteristics:
Foreign institutions/organizations considering applying to this RFA must demonstrate an ability to conduct the proposed study in the designated setting(s) as well as an ability to meet government clearance requirements.
1.B. Eligible Individuals
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.
2. Cost Sharing
Cost sharing is not required.
3. Other-Special Eligibility Criteria
Investigators may submit more than one application, providing there is no scientific or budgetary overlap.
Section IV. Application and Submission Information
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:
Francisco O. Calvo, Ph.D
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard , Rm. 752
Bethesda , MD 20892-5452
(for express/courier service: Bethesda , MD 20817 )
Telephone: (301) 594-8897)
Email: fc15y@nih.gov
3.B. Sending an Application to the NIH
Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:
Francisco O. Calvo, Ph.D
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard , Rm. 752
Bethesda , MD 20892-5452
(for express/courier service: Bethesda , MD 20817 )
Telephone: (301) 594-8897)
Email: fc15y@nih.gov
Using the RFA Label: The RFA label available in the PHS 398 application instructions 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://grants1.nih.gov/grants/funding/phs398/labels.pdf.
3.C. Application Processing
Applications must be received on or before the application receipt date listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review. Applications will be evaluated for completeness by CSR.
Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK Review Branch . Incomplete and non-responsive applications will not be reviewed.
The NIH will not accept any application in response to this funding opportunity 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 a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity 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.
Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.
4. Intergovernmental Review
This initiative is not subject to intergovernmental review.
5. Funding Restrictions
All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm (see also Section VI.3. Award Criteria).
6. Other Submission Requirements
1. This RFA requires a collaborative research project with two or three PIs to foster cross-disciplinary work. The investigators do not need to be at the same institution. For these collaborative projects, the individual components must be submitted as one packet accompanied by a cover letter that lists the principal investigators, their institution(s), and their identical project titles. To facilitate proper processing and review, include this letter with each of the individual applications, and, in each grant application, list the collaborating projects and principal investigators on page 2, under Performance Sites. In addition, the DESCRIPTION (page 2) for each grant application within a collaborative project should be the same and the applicants should define in the DESCRIPTION how and why the individual participants propose to collaborate.
2. The RESEARCH PLAN section should be included in ONLY one of the grant applications. All of the remaining grant applications within the collaborative project should refer to the RESEARCH PLAN from the designated application, rather than duplicate the RESEARCH PLAN. The significance and nature of the collaboration should be explained in the Introduction section of the RESEARCH PLAN.
3. Those collaborative applications that do not include, but only refer to, the RESEARCH PLAN must include the following info rmation in their application: Face Page, DESCRIPTION, Performance Sites, and Key Personnel, Research Grant Table of Contents, Modular budget, Budget Justification, Biographical Sketches of PI and other Key Personnel, Resources and Environment, and Checklist. Sections for Human Subjects Research and/or Vertebrate Animals must also be completed, if appropriate.
4. 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. Projects that are not funded in the competition described in this RFA may be restructured and designed as a traditional R01 application, and submitted as NEW applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application at: http://grants.nih.gov/grants/funding/phs398/phs398.html
5. Upon initiation of the program, the participating Institutes 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 will take place about six months after the award is issued.
Specific Instructions for Modular Grant applications.
Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget 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 budgets. Additional info rmation on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm .
Section V. Application Review Information
Collaborative grant applications will NOT be reviewed individually, but as components of a single research project, and, as such, the individual applications within a collaborative project will be assigned the same priority score and receive the same reviewers' comments within the individual summary statements.
2. Review and Selection Process
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 NIDDK Review Branch in accordance with the review criteria stated below.
As part of the initial merit review, all applications will:
3. Merit Review Criteria
The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.
1. Significance . Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
2. Approach . Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?
3. Innovation . Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?
4. Investigators . Are the investigators 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? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Does the collaborative group merge scientific expertise based upon strong experimental rationale and sound project goals? Previous collaborations between the investigators are not required because a purpose of this RFA is to recruit new investigators into the field of diabetes complications.
5. Environment . Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?
3.A. Additional Review Criteria:
In addition to the above criteria, the following items will continue to 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 the Research Plan, Section E on Human Subjects in the PHS Form 398).
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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).
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 Form 398 research grant application instructions will be assessed.
3.B. Additional Review Considerations
Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.
Section VI. Award Administration Information
4. Reporting
Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.
Merrill M. Mitler, Ph.D.
National Institute of Neurological Disorders and Stroke
Neuroscience Center , Rm. 2108
6001 Executive Blvd.
Bethesda , MD 20892
Phone: (301) 496-9964
Fax: (301) 402-2060
E-mail: mm777k@nih.gov
Stephen S. Goldman, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10193 , MSC 7956
Bethesda , MD 20892-7956 (FEDEX 20817)
Tel: 301-435-0560
Fax: 301-480-2858
E-mail: sg42r@nih.gov
Peter A. Dudley, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
Bethesda , MD 20892-7164
Telephone: (301) 451-2020
FAX: (301) 402-0528
Email: pd8n@nih.gov
2. Peer Review Contacts:
Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard , Rm. 752
Bethesda , MD 20892-5452
Telephone: (301) 594-8897)
Email: fc15y@nih.gov
3. Financial or Grants Management Contacts:
Kathleen J. Shino, M.B.A.
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard , Rm. 708
Bethesda , MD 20892-5456
Telephone: (301) 594-8869
Email: ks48e@nih.gov
Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center , Room 3290
6001 Executive Blvd.
Bethesda , MD 20892
Phone: (301) 496-9231
Fax: (301) 402-0129
E-mail: dc55g@nih.gov
Owen Bobbitt
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive , Room 7044
Bethesda , MD 20892-7926
Telephone: 301-435-0177
FAX: 301-480-0422
E-mail: ob5i@nih.gov
William Darby
Grants Management Officer
National Eye Institute
Suite 1300
5635 Fishers Lane
Bethesda , Md 20892
Email: wd8u@nih.gov
Section VIII. Other Information
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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