Administrative Supplements for a Drug Screening Program for Diabetic Complications

Notice Number: NOT-DK-05-017

Key Dates
Release Date: August 17, 2005
Request Receipt Date: December 1, 2005
Earliest Award Date: January 31, 2006

Issued by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), (
National Heart, Lung and Blood Institute (NHLBI), (
National Cancer Institute (NCI), (
National Eye Institute (NEI), (
National Institute of Neurological Disorders and Stroke (NINDS), (

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute (NCI), the National Eye Institute (NEI) and the National Institute of Neurological Disorders and Stroke (NINDS) request applications for administrative supplements to NIH-funded grants from the participating institutes to participate in a collaborative program to discover new drugs for the treatment of diabetic complications by screening FDA-approved compounds in assays for hyperglycemic cellular injury (HCI) and other effects of diabetic complications.

Background and Purpose

Type 1 diabetes is an autoimmune disease characterized by destruction of pancreatic beta cells that leads to a loss of insulin production and the resultant hyperglycemia and other metabolic defects. Over time these metabolic abnormalities lead to cell and tissue injury and eventually diseases such as heart attacks, stroke, renal failure, peripheral and autonomic neuropathy and blindness. Clinical studies, such as the Diabetes Control and Complications Trial (DCCT) have demonstrated that tight glycemic control can dramatically reduce the micro- and macrovascular complications of diabetes. However, intensive glycemic control is difficult to obtain in all patients and is associated with an increased risk of hypoglycemia. An important, but elusive, goal for diabetes care has been therapeutics that would prevent or reverse the cellular injury induced by hyperglycemia. Research on hyperglycemic cellular injury (HCI) has increased our knowledge of the pathologic pathways, but translation of this knowledge to clinically useful drugs has been largely unsuccessful.

This announcement seeks a new approach to this problem by requesting applications for participation in a collaborative effort to screen a collection of about 1000 FDA-approved compounds over six months in individual laboratories using assays of hyperglycemic cellular injury or other assays relevant to diabetic complications. This program is based on a successful drug screening program for neurodegeneration in NINDS. The purposes of this program are to: 1) encourage laboratory scientists to participate in translational research; 2) highlight the best assays for diabetic complications; 3) uncover new metabolic or signaling pathways involved in the cellular injury of diabetes; 4) discover a new drug for diabetic complications and 5) piggy-back on the knowledge base of these FDA-approved compounds to hasten clinical trials.

Program Description

Supplements to existing NIH-funded grants from the participating ICs will be given to individual laboratories to screen about 1000 FDA-approved compounds in assays of diabetic complications.

Assays - Assays for HCI must be robust, reproducible and, where possible, have a readout that is amendable to automated analysis. The latter is important because the screen of about 1000 compounds must be accomplished in six months. The ability of the assays to accurately mimic aspects of the diabetic state is critical for obtaining meaningful results. The glucose metabolism of transformed cell lines is altered, so without specific modifications or justification, the use of transformed cell lines is not acceptable for this program. For cell-based assays, primary cells from human, large animals or rodents are preferred. Assays that consider the influence of genetic background on phenotype (e.q. by using outbred animal strains or pooling human samples) will be given preference. Assays on cells from humans or animals at different stages or duration of diabetes would also be important for diversity within the program. Examples of types of assays are listed below.

The glucose concentrations used should be in the range seen in individuals with diabetes with a preference for glucose concentrations in the 10-20 mM range and with an allowable limit of 25 mM. The assay should tolerate low concentrations of ethanol and dimethyl sulfoxide (DMSO) because these additives will be needed to solubilize some of the test compounds. The application should include information on the validity and reproducibility of the assay, as well as the cut-offs for a positive result. Please note: these supplements will not support the development of new assays.

Test compounds - A commercially available set of about 1,000 FDA-approved compounds will be selected based on the diversity of drug classes and structures. Drugs that are likely to interfere with assays will be excluded. The compounds will be distributed in a coded form in order to perform the assays in a blinded fashion at one set concentration.

Program organization – After the supplements are awarded, the investigators will receive the coded test compounds and have about six months to perform the assays on the compounds. Any positive result will need to be repeated and a dose/response curve generated. All data will be sent to a central database.

At the end of the supplemental project period (six months from the award date of the supplement), the funding agencies will convene a workshop. This will allow investigators from all the participating laboratories to learn the results of the screening for the entire program. An advantage of this collaborative program will be the ability to immediately compare results among laboratories on different assays with the common theme of diabetic complications. Positive results in several different assays or in several compounds of similar activity or structure would immediately strengthen the significance of the findings.

Data sharing – The evaluation of the therapeutic promise of identified compounds can be dramatically facilitated by comparison with results in other assays for HCI. Thus, an important goal of this program is to facilitate the comparison of results across multiple assays. Toward achieving this goal, NIH and the Juvenile Diabetes Research Foundation (JDRF) will assist investigators in coordinating the results of screens funded under this program. Implicit in participation in this program, but which should also be stated in the proposal, is a willingness by the investigator to screen the standard compound set and share their results and details of the assay within this combined group of NIH-funded and JDRF-funded investigators. After the completion of the program, we will post the results and the detailed assay methods through a public-access website, such as PubChem, or possibly publish them in a scientific journal. We will allow a period of 12 months for exclusive data sharing among the participating laboratories.

Budget and Funding Information

NIDDK, NHLBI, NCI, NEI and NINDS intend to commit up to $1.5 million in FY 2006 to fund approximately 15 administrative supplements in response to this announcement. This program will be accomplished in partnership with the JDRF who will issue a Request for Applications concurrently with this Notice. Investigators who are interested in this program, but who are not eligible to receive supplements from NIH should contact Dr. Anthony Horton at JDRF ( about the JDRF RFA.

NIH funded investigators may request up to $75,000 in direct costs as a one time supplement for a period of up to one year. Investigators with grants with that are supported by Research Programs (R), Program Projects and Centers (P) and Cooperative Agreements (U) are eligible to apply. Investigators may propose multiple assays in their request, but only a maximum of one supplement will be given to each investigator, regardless of the number of NIH grants they may have.

The standard rules for applying Facilities and Administration costs will apply to these supplements. The parent grant must be active at the time of the award, but may be in its final year or in a no-cost extension. Supplements are one-time awards and will not extend to subsequent years. The earliest award date is January 31, 2006.

The purchase of services from commercial vendors or institutional facilities to perform the screen with the investigator's assay is acceptable. Requests for salary in proportion to time directly devoted to the supplemental project may be included.

To facilitate the exchange of information among participating investigators, the funding agencies will convene a workshop at the end of the supplemental project period. Travel funds to attend a workshop in Bethesda should be included in the budget.

How to apply:

The receipt date for administrative supplement applications will be December 1, 2005.

Applicants are encouraged to contact Dr. Teresa Jones ( prior to submitting a proposal, if they have any questions.

To apply for an administrative supplement, send the application to Dr. Jones (address below) both as one email attachment and a mailed original application. If the administrative supplement is for a grant supported by NHLBI, NCI, NEI or NINDS, the corresponding Institute's Program Official should be copied on the e-mail application. The business official of the institution should be copied on the email message and co-sign the original request.

The application should include the following parts:

1) The face page of PHS form 398 that includes the following information - citation of this notice, the investigator name, grant number and title, the direct and total amounts requested, name and title of the institutional official, and phone, email, and address information for the PI and institutional official.

2) A letter (with a 5-page limit) describing the assay(s), including an abstract. The description of the proposed assay(s) should include data on reliability, reproducibility, cut-offs for positive results, the experience of the investigator with the assay and its relevance to diabetic complications. The letter should describe the relationship of participation in this program to the scope of the original grant and the strategy for testing 1000 compounds within six months. The data sharing aspects of the program should be acknowledged.

3) Specific Aims of the original grant. The proposed work should be within the general scope of an existing, funded NIH grant from the participating institutes.

4) A justification for the budget request with a detailed budget page (page 4 of PHS form 398).

Review Procedure:

The participating institutes will consider supplement requests from all eligible applicants.

Requests will be evaluated according to the following criteria:

Supplement requests will be reviewed by a committee of NIH program staff and outside experts, if needed. Award decisions will be based upon the criteria provided above, availability of funds, and program balance. Given the collaborative nature of this program, a minimum number of 20 investigators from the combined NIH and JDRF programs are required to start this program.


Direct questions about the scientific/research issues of the program to:

Teresa L. Z. Jones, MD
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases/NIH
6707 Democracy Plaza, Room 609
Bethesda, MD 20892-5460
(For FedEx and UPS, use Bethesda, MD 20817)
Phone: (301) 435-2996
Fax: (301) 480-3503

Cristina Rabadan-Diehl, Ph.D.
Program Official
Vascular Biology Research Program
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute
Rockledge II, Room 10186
6701 Rockledge Drive
Bethesda, MD 20892-7956
Phone: 301-435-0550
Fax: 301-480-2858

Sharon Ross, PhD, MPH
Nutritional Sciences Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room 3157
Bethesda, MD 20892
Telephone: (301) 594-7547

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

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

Direct questions about financial/budget issues to:

Ms. Diana O'Donovan
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Plaza, Room 726
Bethesda, MD 20892-5460
Phone: (301) 594-8868

Mary S. Baylor
Grants Management Officer, Heart Team 
National Heart, Lung, and Blood Inst.
Division of Extramural Affairs
Grants Operations Branch
Two Rockledge Center
6701 Rockledge Drive, Rm. 7162
Bethesda, MD  20892-7926
Phone: (301) 435-0152
Fax: (301) 480-3310 

Shane Woodward
Grants Administration Branch 
National Cancer Institute (NCI)
Fairview Center Building, Suite 300
1003 West 7th St.
Frederick, MD  21701-4106
Phone: 301-846-10177
Fax: 301-846-5720

William Darby
Grants Management Officer
National Eye Institute
5635 Fishers Lane. Suite 1300
Bethesda , MD 20892

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

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