INSULIN SIGNALING AND RECEPTOR CROSS TALK

Release Date:  June 14, 1999 (see replacement PA-03-156)

PA NUMBER:  PAS-99-112

National Institute of Diabetes and Digestive and Kidney Diseases

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

PURPOSE

The purpose of this initiative is to stimulate novel and innovative approaches
that address the role(s) of the insulin receptor in the development, progression
and treatment of diabetes and its complications.

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 PA is related to the priority area of
chronic disabling diseases: diabetes.  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 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 pilot and feasibility (R21) award mechanisms.  Responsibility for the
planning, direction, and execution of the proposed project will be solely that
of the applicant.  Awards will be administered under NIH grants policy as stated
in the NIH 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.

Future unsolicited competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the customary
peer review procedures.  The total requested project period for an application
submitted in response to this PA may not exceed four years (two for the R21). The
earliest anticipated award date is September 30, 2000.

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 http://www.nih.gov/grants/funding/modular/modular.htm

Modular grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year ($100,000 for the R21).  A
typical modular grant application will request the same number of modules in each
year.  R01 applications requesting more that $250,000 in any year must use the
traditional budget format.

FUNDS AVAILABLE

For FY 2000, $1,000,000 will be set aside to fund applications submitted in
response to this PA.  It is anticipated that four to six awards will be made. 
However, this funding level is dependent upon the receipt of applications of high
scientific merit.  For FY 2001 an additional $1,000,000 will be set aside and for
FY 2002 an additional $1,000,000 will be set aside.  Although this program is
provided for in the financial plans of the NIDDK, the award of grants pursuant
to this PA is also contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Diabetes mellitus is characterized by inappropriate regulation of serum glucose
levels.  In Type 1 diabetes an autoimmune attack on the endocrine pancreas
results in progressive and irreversible destruction of the insulin secreting beta
cells.  Loss of insulin action on insulin-sensitive target cell glucose uptake
and metabolism results.  Type 2 diabetes has several etiologies, most often
reflected in cellular resistance to insulin action, also with attendant
alterations in the regulation of serum glucose levels.  Insulin acts through a
disulfide-bonded heterotetrameric cell surface receptor comprised of an
extracellular alpha subunit coupled via disulfide bonds to a transmembrane and
intracellular beta subunit.  Signaling through the insulin receptor occurs
through an intracellular tyrosine kinase domain and resultant phosphorylation of
the receptor, itself, and downstream effector and scaffolding proteins.  These
may include scaffolding proteins such as the Insulin Receptor Substrate (IRS) 1-
4, other proteins containing src-homology domains (SH2/3), protein tyrosine
phosphatases such as PTB-1B, and others.  In Type 1 diabetes, absence of the
ligand with normal cellular receptor structure and function is most often the
cause of the subsequent metabolic defects.  Hormone replacement therapy in the
form of daily insulin injections supplies the ligand for receptor action, though
not necessarily in a normal physiologic fashion.  In Type 2 diabetes, resistance
to the action of insulin often underlies the disease with some of the resistance
due to defects in receptor action.

Numerous other cell surface receptors (CSR) belonging to different classes,
including the growth factor tyrosine kinase, G-protein coupled (GPCR), cytokine,
and Ser/Thr kinase receptor families also signal in insulin target cells and
tissues with potential effects on insulin-dependent cellular processes.  The
insulin receptor also appears to act through small intracellular G proteins, but
in some instances evidence exists for insulin signaling through membrane bound
G-proteins, as well.  Insulin action may also directly counter actions of GPCRs,
especially with regard to generation of cAMP.  Insulin action and that of nuclear
receptors may also interact to produce specific effects in target tissues.  Such
is the case with the peroxisome proliferator-activated receptor gamma (PPARgamma)
in adipose tissue and Type 2 diabetes.  Insulin sensitizers may act at the level
of the PPAR to ameliorate some of the resistance to insulin action.  The role of
the insulin receptor in the pathophysiology of diabetes is illustrated in several
transgenic mouse models, such as a tissue-specific knockout of the IR in beta
cells, which results in the development of Type 2 diabetes.

Often a cellular response represents a net response to the interaction of a
number of signals.  Some of the effects of insulin receptor action can occur
relatively rapidly while others may require longer-term events and include change
in gene expression.  Many of the actions of insulin and its receptor, such as
effects on glucose transporters, have been long under study, but insufficient
progress has been made in understanding underlying mechanisms of action and
role(s) in the pathophysiology of diabetes and its complications.  Moreover,
little is known of the potential effects of disregulated cell signaling on the
development of the complications of diabetes, including the potential effects of
the chronic hyperinsulinemia that accompanies treatment of insulin-dependent
diabetes (Type 1), or is symptomatic of insulin-resistant forms of the disease
(Type 2).  Finally, the role of insulin as a mitogenic factor, effecting change
in gene expression through interactions with transcription factors, remains
little understood.

Thus, the specific objectives of this research solicitation include, but are not
limited to:

o  Determination of the specificity of signaling through the insulin receptor,
including delineation of metabolic versus mitogenic responses

o  Elucidation of the precise mechanism of action of the insulin receptor in
mediating glucose uptake in insulin-sensitive tissues

o  Signaling through growth factor, cytokine or GPCRs in insulin target tissues
and potential role(s) in the pathophysiology of diabetes and its complications

o  Identification of novel factors associated with cell surface receptor action
in insulin target tissues which may be involved in development of diabetes, its
progression; and as putative targets for therapeutic intervention

o  Structural biology of cell surface receptors involved in diabetes and its
complications

o  Delineation of pathways of signaling through the insulin receptor leading to
specific transcription factor(s): role(s) in the development, progression, and
treatment of diabetes

o  Interactions between and among transcription factors that mediate the effects
of insulin on gene expression:  cross-talk with transcription factors responding
to other signaling pathways

o  Signaling cross-talk between the insulin receptor and other classes of cell
surface or nuclear receptors and effects on regulation of the development and/or
progression of diabetes and its complications

o  Factors which regulate expression on the cell surface of functional insulin
receptors, and other CSRs, in diabetes and its complications

o  Identification of factors involved in cell signaling which may cause
resistance to insulin action in target insulin-sensitive cells (e.g. muscle,
adipose) and novel approaches to overcoming or bypassing such resistance

o  The mechanism of action of nonpeptide receptor analogs and potential efficacy
as therapeutic agents

This list of suggested objectives is by no means complete.  Investigators are
encouraged to suggest novel and innovative approaches directed toward
understanding the role of signaling through the insulin receptor in diabetes and
its complications.

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
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:
http://www.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 (revised
4/98) and will be accepted at the standard receipt dates indicated in the
application kit.  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.

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 http://www.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: 
http://www.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 PA 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 a signed, typewritten original of the application, including the
Checklist, and five 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established referral guidelines. 
Applications will be evaluated for scientific and technical merit by an
appropriate peer 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

Award criteria that will be used to make award decisions include:

o  Scientific merit as determined by peer review;
o  Availability of funds;
o  Programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Ronald Margolis, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8819
FAX:  (301) 435-6047
Email:  rm76f@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Charlette Kenley
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8847
FAX:  (301) 594-3504
Email:  KenleyC@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
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.  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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