BIOLOGY OF IRON OVERLOAD AND NEW APPROACHES TO THERAPY

Release Date:  February 3, 1999

RFA: DK-99-009

P.T.

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

Letter of Intent Receipt Date: May 11, 1999
Application Receipt Date: June 11, 1999

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and
the National Heart, Lung and Blood Institute (NHLBI) invite research grant
applications for both basic and clinical research in areas related to
pathogenesis and new therapies for iron overload.  The purpose of this initiative
is to encourage research aimed at developing a better understanding of the
biological consequences of iron overload and improving methods of therapy.  A
major aspect of this initiative is to elucidate the control of iron transport and
metabolism, in order to facilitate the development of improved means of removing
excess iron.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Biology of Iron Overload and New
Approaches to Therapy, is related to the priority area of chronic disabling
conditions. Potential applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and non-profit
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

Support of this program will be through the National Institutes of Health (NIH)
research project grant (R01).  Investigators without prior R29 or R01 support are
encouraged to apply for this RFA and to identify their status on the front of the
grant application.  Specific R01 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, applicant institutions, reviewers, and
Institute staff.  Although multidisciplinary approaches are encouraged, it is not
the intent of this RFA to solicit applications for large studies encompassing a
variety of individual subprojects, i.e., program projects.  If collaborative
arrangements through subcontracts with other institutions are planned, consult
the program staff listed under INQUIRIES.

For this RFA, funds must be requested in $25,000 direct cost modules and a
maximum of eight modules ($200,000 direct costs) per year may be requested.  A
feature of the modular grant concept is that no escalation is provided for future
years, and all anticipated expenses for all years of the project must be included
within the number of modules being requested.  Only limited budgetary information
will be required and any budget adjustments made by the Initial Review Group will
be in modules of $25,000.  Instructions for completing the Biographical Sketch
also have been modified.  In addition, Other Support information and the
application Checklist page are not required as part of the initial application. 
If there is a possibility for an award, necessary budget, Other Support and
Checklist information will be requested by Institute staff following the initial
review.

The APPLICATION PROCEDURES section of this RFA provides specific details of
modifications to standard PHS 398 application kit instructions.  Applicants are
expected to furnish their own estimates of time required to achieve the
objectives of the proposed research project.  Since a variety of approaches would
represent valid responses to this RFA, it is anticipated that there will be a
range of costs among individual grants awarded.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that of the
applicant.  Awards will be administered under PHS grants policy as stated in the
PHS Grants Policy Statement.

Applicants from institutions that have a General Clinical Research Center (GCRC)
funded by the NIH National Center for Research Resources may wish to identify the
GCRC as a resource for conducting the proposed research.  If so, a letter of
agreement from either the GCRC program director or principal investigator should
be included with the application.

This RFA is a one-time solicitation.  Future unsolicited competing continuation
applications will compete with all investigator-initiated applications and will
be reviewed according to the customary peer review procedures.  The total
requested project period for an application submitted in response to this RFA may
not exceed five years.  A maximum of five years can be requested for foreign
awards.  The anticipated award date is April 1, 2000. 

FUNDS AVAILABLE

For FY 2000, $2,000,000 will be committed by the NIDDK to fund applications
submitted in response to this RFA.  The NHLBI will contribute $1,000,000.  It is
anticipated that up to 18 awards will be made.  Funding is dependent upon the
receipt of applications of high scientific merit.  Although this program is
provided for in the financial plans of the NIDDK and the NHLBI, the award of
grants pursuant to this RFA is contingent upon the availability of funds for this
purpose.  

RESEARCH SCOPE AND OBJECTIVES

Iron is indispensable for life, exerting its function either in the form of non-
heme iron-containing proteins or as the iron-protoporphyrin complex of heme
proteins.  Iron-containing proteins catalyze many essential reactions of energy
metabolism.  Most of the iron in the body is located in the erythron, defined as
the totality of all erythroid elements at all sites of the body, including the
marrow, circulation, and the extravascular space.  The main pathway of internal
iron flux is unidirectional, from transferrin (the predominant iron carrier) to
the erythron, to the monocyte-macrophage system and back to plasma transferrin. 
Iron is cycled very efficiently from recently destroyed erythrocytes to newly
formed erythrocytes.  Under physiologic conditions the body is in iron balance. 
Because humans are unable to excrete excess iron, balance is regulated through
the control of iron absorption, mainly by the cells of the intestinal mucosa. 
Mucosal iron absorption is influenced principally by the amount of stored iron
and by the level of erythropoietic activity.

Iron overload arises when the amount of iron entering the body exceeds the amount
lost over a sustained period of time.  Iron overload develops when the regulatory
function of the intestinal absorption is altered, as in hereditary
hemochromatosis, or when absorption is circumvented, as in transfusional iron
overload.  The identification in late 1996 of the gene responsible for most
hereditary hemochromatosis represents a major breakthrough, and creates a strong
impetus for substantial advances in the understanding at the molecular level of
the mechanisms of iron transport and the cellular regulation of iron metabolism.
It is to be anticipated that these studies will lead to therapeutic strategies
to manipulate iron uptake and iron concentrations in cellular compartments,
interventions of potential relevance in a variety of disease states, including
hemochromatosis, transfusion-dependent thalassemia, chronic renal failure,
methods for dealing with intracellular pathogenic organisms and possibly some
autoimmune disorders.  Investigation in this area can profitably address a number
of goals, including but not limited to characterization of the structural
features of iron transporters in the gastrointestinal tract, elucidation of the
process of iron recycling in the reticuloendothelial system and clarification of
the mechanism of action of the hereditary hemochromatosis protein in iron
metabolism.

An adequate transfusion program can markedly improve the quality of life and life
expectancy in patients with severe anemia, but does so at the price of a
progressive iron overload through accumulation of the iron carried by the
transfused red cells.  Since humans do not possess a physiologic means of
excreting excess iron, the accumulation of iron within tissues from repeated
transfusion results in progressive organ dysfunction in the absence of chelating
therapy.  The application of iron chelating therapy has resulted in significantly
reduced morbidity and mortality in compliant transfused patients.  However, many
problems exist with chelation therapy including high cost, discomfort in
administration, and noncompliance.  Research aimed at the development of new iron
chelating drugs has not led to an acceptable alternative to the only clinically
approved drug, deferoxamine.  Advances related to an increased understanding of
molecular and biochemical pathways of iron metabolism, understanding of
fundamental mechanisms of iron chelator action, and improved rational drug design
techniques may offer an opportunity to undertake a more systematic approach to
this problem.

It is clear that improved understanding of intestinal iron absorption and
elucidation of mechanisms of systemic iron recycling are promising areas where
increased understanding may improve our ability to treat iron overload disorders. 
A variety of models of intestinal iron uptake have been proposed, but none has
met with universal acceptance.  Research should be directed towards understanding
the precise mechanism of intestinal iron transport, identification of the
transporter itself, and accessory molecules that may be involved (e.g., ferric
reductase, ferric oxidase).  The elucidation of the mechanisms of regulation of
intestinal iron transport by the hemochromatosis gene (designated HFE) protein,
by hypoxia, and by a bone marrow-to-enterocyte signal in ineffective
erythropoiesis represent significant issues.  Attempts might be made to identify
agents that specifically block the intestinal iron transporter and/or the
proteins that regulate it.  In the long term, increased knowledge in these areas
should lead to new therapies to block or augment intestinal iron uptake. Thus the
areas of research within this announcement include, but are not restricted to:

o  Basic mechanisms of the control of iron uptake and release from cells under
normal and iron overloaded conditions.

o  The nature of the ionic species of iron released by the gut and macrophages.

o  The role of heme-iron absorption in iron overload.

o  Genetics and control of expression of iron proteins and their role in
transport.

o  Examination of non-hepatic iron metabolism.

o  Delineation of iron transport pathways that may be affected by iron chelators.

o  Exchange of iron among the various cellular compartments under normal
conditions and in response to chelation.

o  Mechanisms of iron chelator toxicity.

o  Means to enhance iron excretion or to limit iron absorption.

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
sub-populations 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/not94-105.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.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 11, 1999, a letter of intent
that includes a descriptive title of the proposed research; the name, address,
and telephone number of the Principal Investigator; the identities of other key
personnel and participating institutions; and the number and title of the RFA in
response to which the application may be submitted.

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 NIDDK staff to estimate the potential review workload and avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and 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. The forms are also available online at:
https://grants.nih.gov/grants/funding/phs398/phs398.html

The RFA label available in the PHS 398 (rev. 4/98) application form must be
affixed to the bottom of the face page of the application.  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.

This RFA is restricted to R01 grants.  All will be awarded as modular grants. 
The modular grant concept establishes specific modules (increments) in which
direct costs may be requested and a maximum level for requested direct cost. 
Only limited budgetary information is required in the application; a detailed
budget need not be provided.

Sample budgets and justification page will be provided upon request, from Ms.
Aretina Perry-Jones at the address listed under INQUIRIES or following the
submission of a letter of intent.

BUDGET 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:

o  FACE PAGE

As a reminder, Item 7 should be completed to indicate Modular Direct Costs
requested and Item 8 should reflect Total Costs (Modular Direct plus F&A costs).

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD

Do not complete Form Page 4 of the PHS 398 (rev 4/98).  It is not required nor
will it be accepted at the time of application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT

Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev.
4/98). Only the requested total direct costs line for each year must be completed
based on the number of $25,000 modules being requested.  Applicants may not
request a change in the amount of each module.  A maximum of EIGHT modules
($200,000 direct costs) per year may be requested and each applicant may request
up to FIVE years of support for this RFA.  Direct cost budgets will remain
constant throughout the life of the project (i.e., the same number of modules
requested for all budget periods).  Any necessary escalation should be considered
when determining the number of modules to be requested.  However, in the event
that the number of modules requested must change in any future year due to the
nature of the research proposed, appropriate justification must be provided. 
Total Direct Costs for the Entire Proposed Project Period should be shown in the
box provided.

o  BUDGET JUSTIFICATION

-  Budget justifications should be provided under "Justifications" on Form Page
5 of the PHS 398.

-  List the names, role on the project and proposed percent effort for all
project personnel (salaried or unsalaried) and provide a narrative justification
for each person based on his/her role on the project.  UNDER THE JUSTIFICATION
FOR THE PRINCIPAL INVESTIGATOR, INDICATE IF YOU ARE A NEW INVESTIGATOR  (i.e.,
AN INVESTIGATOR WITHOUT PRIOR R29 OR R01 SUPPORT).

-  Identify all consultants by name and organizational affiliation and describe
the services to be performed.

-  Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.  More
detailed justifications should be provided for high cost items.  Any large one-
time purchases, such as large equipment requests, must be accommodated within
these limits.  No specific costs for items or categories should be shown.

o  CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are involved
that require transfer of funds from the grantee to other institutions, it is
necessary to establish formal subcontract agreements with each collaborating
institution.  A letter of intent from each collaborating institution should be
submitted with the application.  Only the percentage of the
consortium/contractual TOTAL COSTS (direct and indirect) relative to the total
DIRECT COSTS of the overall project needs to be stated at this time. The
following example should be used to indicate the percentage cost of the
consortium, "The consortium agreement represents 27% of overall $175,000 direct
costs requested in the first year."  A budget justification for the consortium
should be provided as described in the "Budget Justification" section above (no
Form Page 5 required for the consortium).  Please indicate whether the consortium
will be in place for the entire project period and identify any future year
changes in the percentage relative to the parent grant.

If there is a possibility for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the consortium. 
Please note that total subcontract costs need not be calculated in $25,000
modules.  However, when subcontract funds are added to the parent grant budget,
the total direct cost amount must be included in the number of $25,000 modules
requested.

o  BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel,
following the modified instructions below.  Do not exceed the two-page limit for
each person.
-  Complete the education block at the top of the form page;
-  List current position(s) and those previous positions directly relevant to the
application;
-  List selected peer-reviewed publications directly relevant to the proposed
project, with full citation;
-  The applicant has the option to provide information on research projects
completed and/or research grants participated in during the last five years that
are relevant to the proposed project.

o  OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). 
Selected other support information relevant to the proposed research may be
included in the Biographical Sketch as indicated above. Complete Other Support
information will be requested by Institute staff if there is a possibility for
an award.

o  CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by Institute staff if there
is a possibility for an award.

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.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE
TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

Submit a signed, typed original of the application, including the Checklist, plus
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 time of submission, two additional copies of the application and all copies
of appendix material must be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600

Applications must be received by June 11, 1999.  If an application is received
after that date, it will be returned to the applicant without review.
Supplemental documents containing significant revisions or additions will not be
accepted unless applicants are notified by the Scientific Review Administrator. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The CSR
will not accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of substantial revisions of
applications previously reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group in accordance
with the review criteria stated below.  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 the applications under review, will be discussed, assigned a priority
score, and receive a second level review by the National Diabetes and Digestive
and Kidney Diseases Advisory Council and by the National Heart, Lung and Blood
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, 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 that are not readily available in the United States or which
provide augmentation of existing U.S. resources.

AWARD CRITERIA

The earliest anticipated date of award is April 1, 2000.  Applications will
compete for available funds with all other applications submitted in response to
this RFA and recommended by peer review.  The following will be considered in
making funding decisions: quality of the applications as determined by peer
review; availability of funds; and program needs and balance.

INQUIRIES

Inquiries concerning this RFA 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:  badmand@extra.niddk.nih.gov

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

Direct inquiries regarding fiscal and administrative 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
Email:  perrya@extra.niddk.nih.gov

Ms. Jane Davis
Division of Extramural Activities
National Heart Lung 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 Domestic Assistance No.
93.847 and 93.839.  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.  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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