NIH Guide: HEMOCHROMATOSIS AND DIABETES MELLITUS

HEMOCHROMATOSIS AND DIABETES MELLITUS

Release Date: February 9, 2000

PA NUMBER: PA-00-055

National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung and Blood Institute

THIS PA USES THE "MODULAR GRANT" AND JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE
USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
and the National Heart, Lung and Blood Institute (NHLBI) invite investigator-
initiated research grant applications to study the molecular mechanisms
underlying the pathogenesis of diabetes mellitus in hemochromatosis and other
forms of iron overload, and to encourage clinical studies leading to a better
understanding of the development of diabetes in patients with iron overload.

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 PA, The Role of Growth
Factors in the Development of Diabetes Complications, is related to the
priority area of diabetes and chronic disabling conditions. Potential
applicants may obtain a copy of "Healthy People 2010" at
http://odphp.osophs.dhhs.gov/pubs/hp2000

ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign for-profit and
nonprofit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal Government. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as principal
investigators.

MECHANISM OF SUPPORT
This PA will use the National Institutes of Health (NIH) research project
grant (R01) and Exploratory/Development Research Grant (R21) award
mechanisms.

The R21 awards are to demonstrate feasibility and to obtain preliminary data
testing innovative ideas that represent clear departure from ongoing research
interests. These grants are intended to 1) provide initial support for new
investigators; 2) allow exploration of possible innovative new directions for
established investigators; and 3) stimulate investigators from other areas to
lend their expertise to research within the scope of this solicitation.
Applicants for the R21 must limit their requests to $100,000 direct costs per
year and are limited to two years. These R21 grants will not be renewable;
continuation of projects developed under this program will be through the
regular research grant (R01) program). NHLBI will accept assignment only of
RO1 applications. Applicants interested in submitting R21 applications may
wish to seek guidance from Institute Program Directors listed under
INQUIRIES.

This PA will use the modular grants application and award process. Specific
application instructions have been modified to reflect "MODULAR GRANT" and
"JUST-IN-TIME" streamlining efforts being examined by the NIH. The modular
grant concept establishes specific modules in which direct costs may be
requested as well as a maximum level for requested budgets. Only limited
budgetary information is required under this approach. The just-in-time
concept allows applicants to submit certain information only when there is a
possibility for an award. It is anticipated that these changes will reduce
the administrative burden for the applicants, reviewers and Institute staff.
Refer to instructions under APPLICATION PROCEDURES, below. Complete and
detailed instructions and information on Modular Grants can be found at
https://grants.nih.gov/grants/funding/modular/modular.htm

Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant. The NIH Grants policy
statement applies to these awards.

RESEARCH OBJECTIVES

Background

Hereditary hemochromatosis is the most common genetic disorder known in the
United States. As much as 10 percent of the population is heterozygous for
this condition, and the homozygous state is believed to affect as much as 0.5
percent of the population, or more than one million people. In affected
individuals, inappropriately increased absorption of iron may result in its
progressive accumulation in the liver, heart, pancreas and other organs,
eventually producing hepatic cirrhosis, cardiac failure, diabetes mellitus,
arthritis, gonadal dysfunction and other disorders. The identification of
the gene, now designated as HFE, that is mutated in most patients with
hereditary hemochromatosis has been a major advance that has resulted in a
diagnostic genotypic test for this form of iron overload. Population studies
suggest that the disorder is greatly under-diagnosed. Diabetes mellitus is a
major complication of hemochromatosis and virtually all the secondary
manifestations of diabetes may develop, including retinopathy, nephropathy,
neuropathy and vascular disease.

At the basic science level, the molecular mechanisms underlying the
pathogenesis of diabetes mellitus in all forms of iron overload remain
obscure. Iron-induced, free radical mediated damage to the pancreatic beta-
cell has been postulated but careful studies in this area are lacking,
hindered, in part, by the lack of a suitable animal model. Some data suggest
that insulin resistance and beta-cell dysfunction in patients with iron
overload develop well before insulin deficiency and are still reversible with
iron depletion. Iron overload as a potentially reversible cause of diabetes
needs more careful examination.

Clinically, the discovery of the gene, HFE, responsible for most cases of
hereditary hemochromatosis, has revolutionized both the understanding and
diagnosis of this disorder and created new opportunities for studies of
diabetes as one of the major complications of the disease. In patients with
hemochromatosis, the development of diabetes is an irrevocable step in
disease progression that leads to premature death, even if the excess iron is
subsequently removed. Conversely, hereditary hemochromatosis is a
preventable cause of diabetes mellitus. If patients are identified before
the development of glucose intolerance, removal of the excess iron can
prevent the subsequent development of diabetes. Because of the importance of
hemochromatosis as an often unrecognized cause of diabetes and because of the
significance of diabetes as a critical complication in hemochromatosis,
clinical studies are needed. These may include (i) determination of the
prevalence of hereditary hemochromatosis as an undiagnosed cause of diabetes
mellitus, (ii) determination of the prevalence of HFE mutations (both
heterozygous and homozygous) in patients with diabetes, (iii) development of
new strategies for the management of diabetes in patients with
hemochromatosis.

Objectives and Scope

Appropriate topics for investigation would include, but are not limited to:

o Epidemiological investigations of the relationship between body iron
burden, HFE mutations, especially Cys282Tyr and His63Asp, glucose tolerance,
insulin sensitivity and diabetes.

o Elucidation of the cellular and molecular mechanisms underlying the
pathogenesis of diabetes mellitus in (or associated with) iron overload
disorders.

o The potential role of iron-induced, free radical or lipid peroxidation-
mediated damage to the pancreatic beta-cell and to hepatocytes.

o Effects of increased body iron burden on insulin resistance and glucose
transporter function in several insulin target cells: e.g., muscle,
adipocyte, hepatocyte. A number of reports suggest that increased iron leads
to insulin resistance but the mechanisms responsible for this resistance are
obscure.

o Investigations of differential gene transcription/translation in beta
cells, hepatocytes and enterocytes caused by exposure to elevated iron.

o Investigation of the effectiveness of iron chelation therapy in preventing
or reversing iron-overload mediated diabetes.

o Investigations of ceruloplasmin status vs. the incidence of diabetes. It
is clear that patients with aceruloplasminemia get diabetes and that this
condition is associated with parenchymal iron accumulation, but it is not
known whether quantitative (or functional) variations in ceruloplasmin might
have similar but less obvious effects.

o Studies of the natural history of diabetes associated with hemochromatosis.

o Since individuals at risk can be identified early, serial metabolic
characterizations before and early in the disease to define the initial
events in progression to diabetes are of interest.

o Examination of insulin resistance to learn if it is caused by
hemochromatosis or if people with both conditions are more likely to progress
to diabetes.

o Study of the extent to which diabetes is reversible when iron overload is
corrected.

o Development of suitable animal models for study of diabetes of iron
overload.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of
the research. This new policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of NIH 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 was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators may also obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit. Application kits are available at most institutional
offices of sponsored research, or may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, email: GrantsInfo@nih.gov.

Applicants planning to submit an investigator-initiated new (type 1)
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact NIH
program staff before submitting the application, i.e., as plans for the study
are being developed. Furthermore, the application must obtain agreement from
the staff that the NIH will accept the application for consideration for
award. Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute or Center who agreed to accept
assignment of the application. This policy requires an applicant to obtain
agreement for acceptance of both any such application and any such subsequent
amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at
https://grants.nih.gov/grants/guide/notice-files/not98-030.html

The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and Institute
staff. The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for these grants, with the modifications noted below.

SPECIAL INSTRUCTIONS FOR MODULAR GRANT APPLICATION PROCEDURES

Budget Instructions

Modular Grant applications will request direct costs in $25,000 modules, up
to a total direct cost request of $250,000 per year. (Applications that
request more than $250,000 direct costs in any year must follow the
traditional PHS 398 application instructions.) The total direct costs must be
requested in accordance with the program guidelines and the modifications
made to the standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular
Total Direct plus Facilities and Administrative (F&A) costs] for the initial
budget period Items 8a and 8b should be completed indicating the Direct and
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for
sample pages.) At the top of the page, enter the total direct costs requested
for each year. This is not a Form page.

o Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the
nearest $1,000. List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project. Indicate whether the collaborating institution
is foreign or domestic. The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.
Include the Letter of Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a
specific role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three pages
may be used for each person. A sample biographical sketch may be viewed at:
https://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.

o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

The program announcement title and number must be typed on line 2 of the face
page of the application form and the YES box must be marked.
Submit the signed, original, single-sided application, including the
Checklist, along with five signed photocopies and five collated sets of
appendix materials 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)

The Center for Scientific Review (CSR) will not accept any application in
response to this PA 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.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established NIH referral
guidelines. Applications will be evaluated for scientific and technical
merit by an appropriate scientific review group convened in accordance with
the standard NIH peer review procedures. As part of the initial merit
review, all applications will receive a written critique and undergo a
process in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under review, will
be discussed, assigned a priority score, and receive a second-level review by
the appropriate national advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewer will be asked to discuss the following aspects
of the application 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 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.

o 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?

o 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?

o Innovation: Does the project employ novel concepts, approaches, or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

o 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)?

o 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?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o Adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research. Plans
for the recruitment and retention of subjects will also be evaluated.

o The reasonableness of the proposed budget and duration to the proposed
research.

o The adequacy of the proposed protection of humans, animals, or the
environment, to the extent that they may be adversely affected by the project
proposed in the application.

o Availability of special opportunities for furthering research programs
through the use of unusual talent resources, populations, or environmental
conditions in other countries which are not readily available in the United
States or which provide augmentation of existing U.S. resources.

AWARD CRITERIA

The following will be considered in making funding decisions:

o Quality of the proposed project as determined by peer review;
o Availability of funds;
o Program priority.

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. David G. Badman
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13C MSC 6600
Bethesda, MD 20892-6600
Telephone: (301) 594-7717
FAX: (301) 480-3510
Email: db70f@nih.gov

Dr. Charles M. Peterson
Blood Diseases Program
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Telephone: (301) 435-0051
FAX: (301) 480-0868
Email: PetersoC@gwgate.nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Aretina Perry-Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD 20892-6600
Telephone: (301) 594-8862
FAX: (301) 480-3504
Email: PerryA@extra.niddk.nih.gov

Ms. Jane Davis
Division of Extramural Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive MSC 7950
Bethesda MD 20892-7950
Telephone: (301) 435-0166
FAX: (301) 480-3310
Email: davisj@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Assistance Nos. 93.848
and 93.847. Awards are made under authorization of the Public Health Service
Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
USC 241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject
to the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-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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