This Program Announcement expires on June 1, 2004, unless reissued.


Release Date:  March 19, 2001 (see reissuance PA-05-001)

PA NUMBER:  PA-01-071

National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
Office of Dietary Supplements, Office of the Director, NIH



The objective of this program announcement is to encourage research 
that bridges the areas of inorganic chemistry and medicine.  The 
mechanisms by which organisms control transition metal ions and the 
roles of these metals in cellular regulation and cell-cell signaling 
are of primary interest.  The interactions of synthetic inorganic 
complexes with living systems and their components are a second area of 
interest.  These areas are linked by the need to involve researchers 
having a deep understanding of inorganic chemistry with state-of-the-
art problems in biomedical research.  Much of the work is expected to 
involve collaborations between chemists and biochemists and cell and 
molecular biologists.  The results will be relevant to understanding 
the mechanisms of metal toxicity and the basic cellular roles 
underlying the nutritional requirement for essential metals.  It is 
expected that this research will also contribute to the identification 
of new targets for drug discovery, diagnostics, and future therapeutic 
approaches, although drug development, per se, is not a focus of the 
program at this time.

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 Program 
Announcement (PA), Metals in Medicine, is related to one or more of the 
priority areas.   Potential applicants may obtain a copy of "Healthy 
People 2010" at


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.


This PA will use existing National Institutes of Health (NIH) research 
project grant (R01).  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.

Specific application instructions have been modified to reflect 
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined 
by the NIH. Complete and detailed instructions and information on 
Modular Grant applications can be found at:

Some research efforts may be more appropriate for the Program Project 
(P01) grant mechanism or the Resource-Related Research Project (R24) 
grant mechanism.  Investigators interested in applying for P01 or R24 
grants should contact the Institute program staff listed at the end of 
this announcement.


The objective of this program announcement is to stimulate additional 
research in selected areas of bioinorganic chemistry. The emphasis of 
this announcement is on the ions, complexes, and organometallic 
compounds of the transition metals, post-transition metals, and 
metalloid elements.  Based on input from a broad scientific community, 
NIH held a meeting, entitled, "Metals in Medicine: Targets, 
Diagnostics, and Therapeutics", on June 28 & 29, 2000.  For the program 
and meeting report see:

The goals of this meeting were:  1) to explore the current utilization 
of inorganic chemistry and of basic research discoveries in 
metallobiochemistry by the pharmaceutical industry; and 2) to identify 
areas where additional basic research might enhance the impact of NIH 
support in these areas of science on future health improvements.  

Conclusions from this meeting were in brief:

Metalloenzyme structure/function, mechanism, and inhibition studies are 
currently well supported and produce results that are utilized in the 
design of new diagnostic and therapeutic products.  Additional 
stimulation of this area is not needed.

Metal-containing agents for radiology, radiation therapy, and magnetic 
resonance imaging are expanding areas of activity that will benefit 
from further basic research on metal complexation chemistry and the 
interactions of metal complexes with biological systems.  (Note:  These 
areas are primarily the responsibility of the National Cancer Institute 
and will not explicitly be considered further in this announcement.)

Metal metabolism is an area ripe with opportunities for additional 
research.  Mechanisms of metal homeostasis as well as the roles of 
metals in regulation of cell function and cell-cell interaction are 
areas of potential growth.

Therapeutic applications of metal complexes is an under-developed area 
of research.  Basic principles to guide the development of 
metallopharmaceuticals are lacking.  Metal-containing agents may offer 
unique therapeutic opportunities.  However, significant obstacles, 
including potential metal accumulations and toxicities, require further 
research before the promise of medicinal inorganic chemistry can be 

Based on this meeting and other sources of information, NIGMS, NIDDK, 
NIEHS, and ODS/NIH seek to stimulate additional applications in the 
following areas of research.

A.  Emerging Areas of Metal Metabolism and Regulation.   Metal 
metabolism is emerging as an exciting area of cell biology and a 
potential area for therapeutic intervention.  Normal metal metabolism 
appears to maintain free metal ion concentrations at a very low level 
and to deliver metals very selectively to their sites of action, while 
maintaining tight control over their reactivity. Aberrant metal 
metabolism contributes to pathological conditions such as Menkes' and 
Wilson's diseases, and hemochromatosis.  Intercepting normal metalation 
reactions may be a way to control metalloprotein activity.  Metals have 
also emerged as important sensors and transducers of information with 
roles in regulation. Areas of interest include:

o  Improved metal ion sensors to study cellular metal ion 
concentrations and localization.
o  Reagents suitable to manipulate those concentrations. 
o  Identification and characterization of the macromolecular players 
and vesicular compartments involved in metal ion homeostasis and metal 
o  Elucidation of the roles of metals in cell regulation, signal 
transduction, and cell-cell signaling.
o  Identification and understanding of metal-responsive, oxygen, and 
redox responsive transcriptional and translational regulators, and 
mRNAs and their potential as therapeutic targets.
o  Elucidation of the mechanistic roles of essential trace elements for 
which metabolic functions are not yet clearly established.
o  Analytical tools that accurately monitor biologically important 
pools, storage pools, and the chemical speciation of metals. 
o  Biomarkers of exposure and mechanisms of metal toxicity.
o  Biomarkers for variable susceptibility to metal toxicity in the 
human population.
o  Chelation chemistry that can serve as the foundation for therapies 
to ameliorate aberrant metal accumulations and the effects of toxic 

Basic research is needed to underpin recommendations regarding the 
nutritional importance of metal ions in the diet.  Opportunities for 
research on zinc were highlighted at a meeting organized by the Office 
of Dietary Supplements (ODS), Office of the Director, NIH, and held on 
the NIH campus, Nov. 4-5, 1998.  The proceedings of the meeting were 
published in the Journal of Nutrition, Vol. 130(5s), 1341S-1519S, May, 
2000.  A report of the meeting is available on the ODS web site.  See: Opportunities for 
research on chromium were highlighted at another meeting, also 
organized by the Office of Dietary Supplements, NIH, and held on the 
NIH campus, November 4, 1999.  For a report see:  Of 
particular priority for the NIDDK is research in the areas identified 
as the most productive in accelerating progress relevant to the use of 
chromium supplements in individuals at risk for, or diagnosed with, 
diabetes. The mechanisms of uptake, metabolism, and storage of iron, 
particularly with regard to iron overload and iron chelation, also are 
of considerable priority to the NIDDK. Areas of interest were 
represented at the September 1998 NIDDK meeting “Iron: From Current 
Biochemistry to New Chelator Development Strategies”. For the abstracts 
of this meeting see:

These examples are meant to be illustrative and not meant to single out 
these specific metals as being of exclusive interest.  Similar 
questions about basic understanding of the roles of metals may be 
raised with respect to many other of the essential trace elements.  The 
Office of Dietary Supplements, the NIDDK, and other components of the 
NIH have primary responsibility with respect to human nutritional value 
of metals.  Both NIGMS and NIDDK have a high level of interest in 
understanding the mechanistic roles of essential dietary elements in 
molecular and cellular function.  NIEHS has primary responsibility with 
respect to toxic metal exposure from environmental sources.  Both NIGMS 
and NIEHS have interests in understanding the basic mechanisms of metal 

B.  Interactions of Metal Complexes with Living Systems.  Metal 
complexes may be useful as research probes of biological function, as 
intermediary lead compounds in the development of non-metal containing 
therapeutics, and as potential diagnostic and therapeutic agents.  
Opportunities exist to exploit the unique properties of metal 
complexes, (e.g., hydrolytic and redox activity, Lewis acidity, 
electrophilicity, valency, geometry, magnetic, spectroscopic, and 
radiochemical properties) to measure and/or to alter cellular 
functions.  The actions of these compounds may provide insights that 
are different from those that can be achieved through other chemical, 
biochemical, or genetic manipulations.  Similarly, the actions of metal 
complexes in whole living organisms are expected to differ in general 
from the actions of non-metal containing agents and may offer unique 
research, diagnostic, or therapeutic opportunities.  A goal of this 
program announcement is to utilize the power of inorganic chemistry to 
provide new knowledge of biological systems.  Another goal is to 
improve understanding of the reactions of metal complexes in living 
systems to improve the specificity of these interactions and gain 
control over the potential toxicity of synthetic metal complexes.  The 
long-term goal is to establish the basic principles of an inorganic 
medicinal chemistry that will allow for rational design and screening 
of potential metallopharmaceuticals in the future.  Drug development, 
per se, is not the primary focus of the program at this time.  Areas of 
interest include:

o  Reactions of metal complexes with cellular constituents, e.g., DNA, 
RNA, proteins, lipids, carbohydrates, redox substrates, and signaling 
o  Reactions of metal complexes within the cellular milleu and in vivo.
o  Uptake of metal complexes into cells and delivery to specific 
cellular compartments.
o  Interactions of metal complexes with specific enzymes and receptors.
o  Mechanisms by which synthetic metal complexes recruit cell cycle, 
signal transduction, and other metabolic pathways to alter cell 
o  Structure/activity relationships for ligand design to control metal 
complex activity and stability in vitro and in vivo.

The NIH Metals in Medicine meeting report includes a list of specific 
research opportunities and challenges.  This list is intended to be 
illustrative, not exhaustive.  Investigator-initiated ideas are welcome 
on any subject that will contribute to the objectives of this program 

Research responsive to this announcement may utilize any appropriate 
experimental organisms or model systems.  For some problems, 
interesting discoveries may be found in microorganisms from unusual 
environments and atypical experimental organisms.  For other problems, 
yeast, common invertebrate and vertebrate model organisms, and human 
cell/tissue cultures may be appropriate.  Investigators considering 
human clinical trials are strongly encouraged to contact the program 
staff listed under Inquiries below.


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 are provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of  the research.  This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(; a 
complete copy of the updated Guidelines are available at  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.


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:

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES.  Program staff may also provide 
additional relevant information concerning the policy.


All applications and proposals for NIH funding must be self-contained 
within specified page limitations.  Unless otherwise specified in an 
NIH solicitation, internet addresses (URLs) should not be used to 
provide information necessary to the review because reviewers are under 
no obligation to view the Internet sites.  Reviewers are cautioned that 
their anonymity may be compromised when they directly access an 
Internet site.


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.



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.

Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

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 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 all 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 all 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:

- 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.

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 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:

An applicant 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 the Institute or Center (IC) program staff 
before submitting the application, i.e, as plans for the study are 
being developed.  Furthermore, the applicant must obtain agreement from 
the IC staff that the IC 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

The title and number of the program announcement must be typed on line 
2 of the face page of the application form and the YES box must be 

Submit a signed, typewritten original of the application, including the 
Checklist, and five signed photocopies in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


Applications will be assigned on the basis of established PHS 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 reviewers 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.

(1) 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?

(2) 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?

(3) 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 

(4) 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)?

(5) 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  The 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 in relation 
to the proposed research

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

Additional specific review criteria apply to program project, SBIR and 
award mechanisms.  See the relevant announcements listed above for 


Applications will compete for available funds with all other 
recommended applications. The following will be considered in making 
funding decisions:  Quality of the proposed project as determined by 
peer review, availability of funds, and program priority.


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

Direct inquiries regarding programmatic issues to:

Dr. Peter C. Preusch
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
Building 45, Room 2AS.43C
Bethesda, MD  20892-6200
Telephone:  (301) 594-5938
FAX:  (301) 480-2802

Dr. Maren R. Laughlin
Director, Metabolism Program
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Rm. 6101, MSC 5460
Bethesda, MD  20892-5460
Telephone:  (301) 594-8802
FAX:  (301) 480-3503 

Dr. Claudia Thompson
National Institute of Environmental Health Sciences
MD EC-21, P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4638
FAX:  (919) 541-4606

Dr. Becky Costello
Office of Dietary Supplements
National Institutes of Health
Building 31, Room 1B25
Telephone:  (301) 435-3920
FAX:  (301) 480-1845

Direct inquiries regarding fiscal matters to:

Mr. Joe Ellis
Grants Management Officer
National Institute of General Medical Sciences
Building 45, Room 2AN.24C
Bethesda, MD  20892-6200
Telephone:  (301) 594-5135
FAX:  (301) 480-2554

Ms. Cheryl Chick
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Plaza, Room 606 MSC 5458
6707 Democracy Blvd.
Bethesda, MD 20892-5458
For Courier service, use Zip Code 20817
Telephone:  (301) 594-8825
FAX:  (301) 480-3504

Mr. Dwight Dolby
National Institute of Environmental Health Sciences
MD EC-22, P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-7824
FAX:  (919) 541-2860


This program is described in the Catalog of Federal Domestic Assistance 
No. 93.821, 93.859, 93.862 for NIGMS, 93.113 for NIEHS, and 93.847, 
93.848, 93.849 for NIDDK.  Awards are made under authorization of 
sections 301 and 405 of the Public Health Service Act as amended (42 
USC 241 and 284) and administered under NIH grants policies and Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is not 
subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

The Office of Dietary Supplements (ODS) was mandated by Congress in 
1994 and established within the Office of the Director, National 
Institutes of Health (NIH). The Dietary Supplement Health and Education 
Act (DSHEA) [Public Law 103-417, Section 3.a] amended the Federal Food, 
Drug, and Cosmetic Act “to establish standards with respect to dietary 
supplements”. This law authorized the establishment of the ODS.

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, and 
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 

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
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