Full Text PA-96-049
 
BIOIRON RESEARCH:  ROLE OF MRNA AND PROTEIN STRUCTURE IN IRON NUTRITION AND METABOLISM
 
NIH GUIDE, Volume 25, Number 14, May 3, 1996
 
PA NUMBER:  PA-96-049
 
P.T. 34

Keywords: 
  Metabolism, Mineral 
  Nutrition/Dietetics 
  Nucleic Acid Structure/Function 
  Proteins and Macromolecules 

 
National Institute of Diabetes and Digestive and Kidney Diseases
 
PURPOSE
 
The purpose of this program announcement is to stimulate research on
iron absorption and metabolism.  Iron is central to the health of
humans, the production of animals and plants for human food.  Iron
deficiency affects 30 percent of the world's population.  The
negative impact of iron deficiency on learning adds a new dimension
to the importance of adequate management of iron metabolism.  In
addition to nutritional iron deficiency, pathological conditions
associated with altered iron metabolism include iron overload, anemia
of chronic disease and inflammation, and renal failure requiring
hemodialysis.
 
The objectives of the initiative address three of the current trends
in bioiron research:  (l) mRNA structure/function and regulation; (2)
High resolution analysis of protein structure/function; and (3) Novel
approaches to iron nutrition and metabolism.  Markers of current
interest include ferritin mRNA and protein (iron
concentration/storage), mRNA and protein for iron uptake (transferrin
receptor) and the protein for iron transport (transferrin), as well
as other iron-binding entities including mucins, integrins, and
mobilferrin.
 
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.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock
No.017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-512-1800).
 
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. Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards. 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) individual
research project grant (R01) and FIRST (R29) award mechanisms.
Responsibility for planning, direction, and execution of the proposed
project will be solely that of the applicant.  Because the nature and
scope of the research proposed in response to this PA may vary, it is
anticipated that the size of an award will vary also; however, the
support of requests exceeding the NIDDK average grant size of
$160,000 direct cost for R01 grants would be unusual and require
ample justification.  FIRST (R29) awards are limited to $350,000
direct cost over the five year period.
 
RESEARCH OBJECTIVES
 
Investigations are needed that will lead to a better understanding of
the biochemistry and molecular biology of the proteins of iron
absorption and metabolism including ferritin, the transferrin
receptor, and aminolevulinate synthase in erythroid heme synthesis.
 
The iron regulatory elements (IREs) are encoded in mRNAs with related
regulatory sequences and coordinate protein synthesis in response to
iron.  At least two related proteins, IRPs, interact with the IREs,
as well as initiation factors and, possibly, nucleases, to control
either ribosome binding or mRNA turnover.  The fundamental properties
of IRE/protein interactions provide a unique model for regulation of
eukaryotic mRNA translation and turnover.  The three dimensional
structure of the IRE, the IRPs, and the IRE/IRP complex need to be
determined.  Existing or new  modeling systems should be employed in
an attempt to predict their specific structure(s).  The effect on IRP
or FeS binding on phosphorylation needs to be studied, and the
differences between IRP-1 and IRP-2 should be examined. The mechanism
for iron-dependent mRNA turnover of the transferrin receptor mRNA is
unknown, as is the manner in which iron and the IRP affect initiation
factor and/or ribosome binding to the ferritin or erythroid
aminolevulinate synthase IREs.
 
Developing probes specific for the IRE can lead to rational design of
drugs to regulate iron absorption and metabolism, to enhance ferritin
synthesis in iron overload, and to target any mRNA with a specific
structure that is involved in a pathogenic process.  It is not known
whether or not iron absorption and metabolism can be regulated by
chemicals that have potential activity as drugs targeted to the IRE.
 
Mutation analysis reveals regions in the cell membrane transferrin
receptor required for iron uptake.  High resolution x-ray
crystallography reveals the sites of bound solvent/water important
for reversibly concentrating iron in the interior of ferritin.
Conformational flexibility also has been observed. Mutations that
change receptor function could affect the structure of the
transferrin receptor or of ferritin in an as yet unknown manner.
 
Formal analogies can be drawn between ferritin structure and function
and the channel proteins that transfer sodium, potassium and calcium
across cell membranes. Thus, ideas gained from studying ferritin can
illuminate problems important in membrane function.  It is not known
how protons enter and leave ferritin, nor is the manner in which the
channels operate.  The path of iron ions entering and leaving
ferritin also is unknown.  Since the iron in the center of ferritin
is a solid phase mineral, understanding the reversible transfer of Fe
ions across the ferritin protein has implications for the reversible
transfer of Ca and phosphate from serum to hydroxyapatite mineral.
Thus, study of proteins of iron metabolism can extend to the
physiology of other heavy metals.  Iron release from or solution in
the mineral is little understood, as is the importance of phosphate
in forming and dissolving the mineral in animal ferritin.
 
Cell specific mRNAs are prime candidates for development of specific
targeted drugs.  These mRNAs also have wide shape specificity, in
contrast to DNA, and a relatively small target size, in contrast to
proteins.  The mRNAs important in iron metabolism contain regions of
distinctive shape, which bind regulatory proteins to increase iron
uptake and decrease ferritin synthesis (iron storage) when iron
levels are low.  The reverse occurs when iron is high.  Studies in
progress are planned to determine the actual RNA and protein shapes
involved.  Their reactivity with shape-recognizing chemicals could
help to explain the novel basis of controlling bioiron in cells.
They also could contribute to development of strategies for managing
abnormal iron metabolism, and for rational drug design for specific
mRNA targets, such as those encoding oncogenes and viral proteins.
Shape-recognizing chemicals could be used to target mRNAs such as
ferritin or transferrin receptor in the development of strategies for
managing abnormal iron absorption and metabolism.  Other potential
targets include mRNAs encoding viral or oncogene proteins.
 
Other newly identified iron binding proteins and their manner of
action are of interest.  These include aspects of the pathway leading
to iron absorption, such as mucins, integrins and mobilferrin, known
to be involved with enterocyte function.
 
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) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES. Program staff may also provide
additional relevant information concerning the policy.
 
ANIMAL WELFARE CONSIDERATIONS
 
Investigators are encouraged to consider alternative methods and
approaches in their research grant applications that do not require
the use of whole animals, use alternative species such as nonmammals
or invertebrates, reduce the number of animals required, and
incorporate refinements to procedures that will result in the
elimination or further minimization of pain and distress in animals.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) 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 Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email: [email protected].
 
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.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
Potential R29 applicants should refer to the announcement on
Just-in-Time Procedures for FIRST and Career Awards (NIH Guide for
Grants and Contracts, Vol. 25, No. 10, March 29, 1996)) for
information on recent changes in guidelines for FIRST award format.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established Public
Health Service referral guidelines. Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with 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
 
o  scientific, technical, or medical significance and originality of
proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.
 
For Applications from Foreign Organizations:
 
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 that provide augmentation of
existing U.S. resources.
 
AWARD CRITERIA
 
Applications will compete for available funds with other approved
applications.  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:
 
David G. Badman, Ph.D.
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: [email protected]
 
Inquiries regarding fiscal matters may be directed to:
 
Aretina Perry
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: [email protected]
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.849. 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 PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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