Full Text PA-97-036
NIH GUIDE, Volume 26, Number 4, February 7, 1997
PA NUMBER:  PA-97-036
P.T. 34

  Metabolism, Mineral 
  Chemotherapeutic Agents 

National Institute of Diabetes and Digestive and Kidney Diseases
The purpose of this program announcement is to stimulate basic
research on the biochemistry of iron chelation in iron overloaded
patients.  Transfusional iron overload is a major cause of morbidity
and mortality in patients with thalassemia (Cooley's anemia).  These
patients urgently need a safe, inexpensive, orally active chelating
agent which effectively promotes iron excretion.  This announcement
seeks to encourage research applications which would improve the
basic understanding of iron chelation, and thus would facilitate the
development of new iron chelating drugs.
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
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.
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 proposal 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 would
require ample justification.  FIRST (R29) awards are limited to
$350,000 direct cost over the five year period.
Considerable effort has been directed toward the development of a new
oral iron chelator for the treatment of transfusional iron overload,
particularly for patients with thalassemia (Cooley's anemia).
However, the likelihood of success of this effort remains uncertain.
Basic understanding of chelation needs to be improved in such aspects
as the kinetics of iron chelation, the identity of the iron pools
addressed, and ways to enhance the chelating activity and reduce the
toxicity of known iron chelators.
Renewed efforts are needed to learn more about the biochemistry of
iron chelation in iron overloaded patients.  Despite the lengthy and
active search for an alternative to the only currently available
drug, desferrioxamine B, only a few clinical trials of a limited
nature have been conducted with new candidate drugs  (Olivieri,
et.al., 1995; al-Refaie, et.al., 1995).  The important goal remains
to further the understanding of those characteristics which would
make an iron chelator effective and safe in long term use.  More
detailed analysis of the intracellular pharmacology of potential new
chelators is needed, including organelle uptake and metabolism.
Studies are needed which would help to identify more precisely the
characteristics which determine efficacy and those which are
associated with toxicity.
Potential research topics are described below; however,
investigators are invited to propose other topics for study.
Pathophysiology of iron overload.  There is still a remarkable gap in
our knowledge of what determines the actual tissue damage or
dysfunction.  This may have direct relevance to the choice of
chelator or the way it is administered.  Some have postulated that if
free iron has a major role, an effective chelator must have a
constant presence in the bloodstream (Fosburg and Nathan, 1990).
Harmful iron levels.  Despite various constructs regarding the
level of iron overload that is potentially harmful or definitely
harmful, little is known about the degree of iron overload that is
associated with organ damage in transfusional hemochromatosis.  For
example, the data on liver iron concentrations often used to
determine the effectiveness of investigational chelators is drawn
from the experience with primary hemochromatosis, a disease in which
the major adverse outcome is cirrhosis, not heart failure as in
thalassemia, so that the relevance is uncertain (Nielsen, et.al.,
1996).  Either animal models of transfusional iron overload or
clinical, pathological, and biochemical correlates in humans would be
helpful in addressing this issue.
Measurement of iron overload.  There are clear clinical needs in this
area, since effective removal of iron by chelating drugs requires an
accurate assessment of iron stores in the patient.  Currently, there
are three types of tests available, serum ferritin, biopsy, and the
SQUID device, each with serious practical deficiencies.  Serum
ferritin, which is measured on drawn blood, is highly variable, and
can be used only as a rough indication of the amount of stored iron.
Biopsy of the liver results in accurate information, but can be
performed only 1-2 times per year, at most, while biopsy of the heart
is too risky.  The SQUID device (Brittenham, et.al., 1982, Nielsen,
et.al., 1995), whose development was funded by the NIDDK, gives
accurate results for the liver, but there are only two such devices
in the world, resulting in restricted access.  Biochemical or
physical methods such as MRI for iron determination need to be
developed (Jensen, et.al., 1994).  Particularly needed is a method
for assessing cardiac iron.
Investigation of the cellular origin, biochemistry, and regulation of
serum ferritin.  As alluded to above, despite the clinical importance
of serum ferritin, the most fundamental aspects of its biogenesis,
clearance, normal regulation, and mechanisms for observed
pathological changes remain unknown.  The molecular factors
controlling ferritin biogenesis, release, and clearance via cellular
uptake are unknown, and the molecular structure of serum ferritin and
its relationship to other intracellular ferritins remains undefined.
Because of the possibility that serum ferritin may remain the most
practical means of assessment of iron status for some time to come,
improved understanding of this protein is needed, including the
molecular identification of the cDNAs and genes for serum ferritin,
functional and biochemical properties associated with the protein,
the characterization of its tissue origins, and the elucidation of
the physiological control mechanisms regulating serum ferritin levels
in normal and pathological conditions.
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 20, 1994 (FR 59 1450814513) 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.
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.
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
301/435-0714, email: asknih@odrockm1.od.nih.gov.
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:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
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
The initial review group also will 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.
Applications will compete for available funds with other approved
applications assigned to the National Institute of Diabetes and
Digestive and Kidney Diseases.  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 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: David_Badman@nih.gov
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: PerryA@ep.niddk.nih.gov
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
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.
Olivieri NF, Brittenham GM, Matsui D, Berkovitch M, Blandis LM,
Cameron G, McClelland RA, Liu PP, Templeton DM, Koren G. Iron-
chelation therapy with oral deferiprone in patients with thalassemia
major, N Engl J Med 332(14):918-22, 1995.
Al-Refaie FN, Hershko C, Hofbrand AV, Kosaryan M, Olivieri NF,
Tondury P, Wonke B. Results of long-term deferiprone (L1) therapy: a
report by the International Study Group on Oral Iron Chelators. Brit
J Haematol 91(1):224-9, 1995.
Fosburg, MT and Nathan DG. Treatment of Cooley's anemia, Blood 76(3):
435-444, 1990.
Niederau C;  Fischer R;  Purschel A;  Stremmel W;  Haussinger D;
Strohmeyer G, Long-term survival in patients with hereditary
hemochromatosis, Gastroenterology 110(4):1107-19, 1996.
Jensen PD;  Jensen FT;  Christensen T;  Ellegaard J. Non-invasive
assessment of tissue iron overload in the liver by magnetic resonance
imaging, Brit J Haematol 87(1):171-84, 1994.
Brittenham GM,  Farrell DE,  Harris JW,  Feldman ES,  Danish EH, Muir
WA,  Tripp JH,  Bellon EM, Magnetic-susceptibility measurement of
human iron stores, N Engl J Med 30;307(27):1671-5, 1982.
Nielsen P,  Fischer R,  Engelhardt R,  Tondury P,  Gabbe EE,  Janka
GE, Liver iron stores in patients with secondary haemosiderosis under
iron chelation therapy with deferoxamine or deferiprone, Br J
Haematol 91(4):827-33, 1995.

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