THE EFFECT OF DIABETES ON THE URINARY BLADDER AND ERECTILE FUNCTION

NIH Guide, Volume 26, Number 35, October 17, 1997

RFA:  DK-98-002

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  December 9, 1997
Application Receipt Date:  January 9, 1998

PURPOSE

The National Institute of Diabetes and Digestive and Kidney
Diseases (NIDDK) through its Division of Kidney, Urologic and
Hematologic Diseases (DKUHD) invites investigators to submit
research grant applications which will increase the basic knowledge
of the effects of diabetes mellitus on the lower urinary tract.
Specifically, this request addresses studies of urothelial cell,
vascular, neurological and smooth muscle functions and interactions
in the normal urinary bladder and in penile erectile function and
the changes which occur with diabetes mellitus.  The overall
scientific goal of this initiative is to enhance the understanding
of the molecular and cellular changes which occur in the urinary
bladder and penile erectile function of the person with diabetes. 
The intent of this Request for Applications (RFA) is to intensify
investigator-initiated research, to attract new investigators to
the field, and to increase interdisciplinary research to enhance
the scope and effectiveness of research in this area.

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, The Effect of Diabetes on the Urinary Bladder and
Erectile Function, is related to the priority area of chronic
disabling diseases.  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

Research grant applications may be submitted by domestic and
foreign for-profit and non-profit organizations, public and
private, such as universities, colleges, 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 Grants (R01), Interactive Research
Project Grants (IRPG), and Exploratory Research Grants (R21) award
mechanisms. Potential applicants contemplating the submission of an
IRPG should contact the program official listed under "INQUIRIES"
at an early opportunity.  Guidelines for preparing IRPG
applications are available from the program official or from the
internet at: https://grants.nih.gov/grants/guide/pa-files/PA-96-
001.html.

Applications from Institutions with 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.

Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  Except as
otherwise stated in this announcement, awards will be administered
under Public Health Service (PHS) grants policy as stated in the
PHS Grants Policy Statement.  This RFA is a one-time solicitation. 
Future unsolicited competing continuation applications will compete
with all investigator-initiated applications and be reviewed
according to the customary peer review procedures. Responsibility
for the planning, direction, and execution of the proposed project
will be solely that of the applicant.

R01 applications submitted in response to this RFA may not exceed
five years for the total requested project period.  A maximum of
three years can be requested for foreign awards.  In general, the
maximum budget request for R01 applications should be limited to
$160,000 in direct costs for the initial budget period. Requests
for support that exceeds that amount will require a thorough
justification, and in no case will a request exceeding $250,000
direct costs for the initial budget period will be allowed under
this solicitation.

R21 (Exploratory Research Grant) applications may not exceed three
years for the total project period.  The maximum budget request for
R21 applications may not exceed $75,000 in direct costs for each of
the three budget periods. The R21 grant mechanism should be used
for experienced investigators to develop pilot and feasibility
studies for new and innovative approaches to the study of both the
clinical and basic research aspects of the urologic complications
of diabetes.  These applications generally have very little
supporting pilot data and are reviewed based on the development of
the hypothesis and supporting literature.

The anticipated award date for all grants is July 1, 1998.

FUNDS AVAILABLE

A total of $1.5 million in total costs will be committed by the
NIDDK in 1997 to fund applications of high scientific merit
submitted in response to this RFA.  It is anticipated that 10 to 12
awards will be made.  The number of awards depends on the mix of
R01 and R21 grants awarded.  Although this program is provided for
in the financial plans of the NIDDK, the award of grants pursuant
to this RFA is also contingent upon the availability of funds for
this purpose.

RESEARCH OBJECTIVES

Background:

Diabetes presents a major health care problem for the citizens of
the United States.  It has been estimated that there were
approximately 7.8 million persons in the United States diagnosed
with diabetes in 1993. Neuropathy is a common complication of
diabetes.  In population studies, 30% - 70% of patients were
affected, depending on the neuropathy criteria.  When carefully
studied, the incidence of autonomic neuropathy affecting the
urinary bladder ranges from 27% to 85%.  In addition to autonomic
bladder dysfunction,  there is an increased incidence of asymptotic
and symptomatic bacteria, which can progress to kidney infection
and kidney damage.  This increase in infection has been attributed
to numerous etiologies from incomplete bladder emptying to changes
in cell wall components and immune dysfunctions in the urothelial
cells.

The most common form of organic sexual dysfunction in male
diabetics is erectile impotence.  It has been reported that up to
75% of male patients who have had diabetes for 15 - 20 years suffer
from this.  The molecular and cellular etiology of diabetic
impotence is not known.  It has been ascribed to both vascular and
neuropathic origins.  There are very few published research studies
which address either the clinical aspects of bladder dysfunction in
the diabetic or the basic molecular and cellular aspects of the
diabetic bladder.

A confounding factor for all basic studies on both the bladder and
the mechanism of penile erection is the lack of published data on
urothelial cell, vascular, neurological and smooth muscle function
and interactions in bladder and penile tissues from the non-
diabetic which can be used for a comparison with the diabetic.

Scientific Objectives:

o  To characterize the molecular and cellular aspects of the
urothelial cell, vascular, neurological and smooth muscle functions
and interactions in the normal urinary bladder and the normal
penile corporal tissue.

O  To identify and characterize the cellular and molecular changes
which occur in the diabetic bladder and in corporal tissue from a
diabetic.

o  To develop small, short term, clinical pilot studies to further
characterize the bladder and erectile dysfunction in the diabetic
patient and to test novel treatment strategies.

o  To identify and characterize genetic markers which identify
early disease related effects on bladder and erectile function.

Program Objectives:

o  To increase the diversity of scientific expertise applied to
basic research studies of the urinary bladder and sexual
dysfunction.

o  To involve young investigators in research studies related to
the urinary bladder and sexual dysfunction.

o  To involve experienced investigators from diverse basic and
clinical research areas in research on the urinary bladder and
sexual dysfunction.

o  To increase the understanding of the effects of diabetes on the
cellular components urinary bladder and penile corporal tissue.

Research Scope:

The urinary bladder and the penis are complex organs with many
interacting molecular, cellular and tissue elements.

The scope of this solicitation is meant to encompass all the
molecular and cellular components and interactions which occur both
in the normal organ/tissue and in the diabetic tissue.  Broad areas
for investigation include, but are not limited to:

1. Pathogenic mechanisms
2. Genetic mechanisms
3. Therapeutic strategies
4. Markers of early dysfunction

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 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 have been
published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 9, 1997, 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. 5/95) 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:
asknih@od.nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) 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.

Submit a signed, typewritten original of the application, including
the Checklist, plus three signed photocopies, in one package to:
CENTER FOR SCIENTIFIC REVIEW (formerly 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)

At time of submission, two additional copies of the application
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 January 9, 1998.  If an
application is received after that date, it will be returned to the
applicant without review.  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 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 will
be discussed, assigned a priority score, and receive a second level
review by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.

Review Criteria

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?"

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.

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

Applications will compete for available funds with all 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

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

Inquiries regarding programmatic issues may be directed to either:

Leroy M. Nyberg, Jr., Ph.D., M.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13 - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX: (301) 480-3510
Email:  leroy_nyberg@nih.gov

Ralph L. Bain, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-13 - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  bainr@extra.niddk.nih.gov

Inquiries regarding fiscal and administrative matters may be
directed to:

Trude Hilliard
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38 - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8859
FAX:  (301) 480-3504
Email:  hilliardt@extra.niddk.nih.gov

SCHEDULE

Application receipt dates, initial review, and award cycles will
be:

Letter of Intent Receipt Date:  December 9, 1997
Application Receipt Date:       January 9, 1998
Initial Review:                 March-April 1998
Advisory Council Review:        May 1998
Anticipated Date of Award:      July 1, 1998

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 the PHS mission to protect and advance the physical
and mental health of the American people.

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