INNOVATIVE RESEARCH APPROACHES TO BASIC BLADDER BIOLOGY AND THE PAINFUL BLADDER
SYNDROME

Release Date:  January 22, 1999

RFA:  DK-99-014

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 14,1999
Application Receipt Date:  April 12, 1999

THIS RFA USES THE MODULAR GRANT CONCEPT.  THIS RFA INCLUDES DETAILED
MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN
PREPARING AN APPLICATION IN RESPONSE TO THIS RFA.

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites
investigators to apply for research grants on basic bladder biology and painful
bladder syndrome, including Interstitial Cystitis (IC).  The painful bladder
syndromes are common chronic disorders with persistent and disabling symptoms
that include urinary frequency, urgency and bladder and pelvic pain.  This
solicitation invites applications for basic research studies on the molecular and
cellular biology of the bladder urothelium, mechanisms of pain perception in the
bladder, and the relationship between neuromuscular innervation and bladder
function.  Pilot and feasibility studies in human subjects focusing on innovative
treatments for interstitial cystitis and other syndromes of bladder and pelvic
pain and new markers of disease are also a focus of this initiative.  The overall
goal is to enhance the understanding of the molecular, genetic, and cellular
pathophysiology of the normal urinary bladder and the bladder in painful bladder
syndromes and to develop new and innovative clinical approaches to these
disorders.  The intent of this Request for Applications (RFA) is to intensify
investigator-initiated research, attract new investigators to the field, and
increase interdisciplinary research to broaden 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, Innovative Research Approaches
to Basic Bladder Biology and the Painful Bladder Syndromes, is related to the
priority area of chronic disabling diseases.  Potential applicants may obtain a
copy of "Healthy People 2000 at http://www.crisny.org/health/us/health7.html.

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, and eligible agencies of the Federal government.  Racial/ethnic
minority individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.

Competitive renewal applications (Type 2) and revised applications are not
acceptable for this request.

MECHANISM OF SUPPORT

This program will be supported through National Institutes of Health (NIH)
Research project Grants (R01), Interactive Research Project Grants (IRPG), and
Exploratory Research Grants (R21).  Investigators without prior R29 or R01
support are encouraged to apply for this RFA and to identify their status as new
investigators on the front of the grant application.  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.

Applications from Institutions with a General Clinical Research Center (GCRC)
funded by NIH's 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.

This RFA is a one-time solicitation.  Future unsolicited competing continuation
applications and revised resubmission of applications from this solicitation will
compete with investigator-initiated applications and be reviewed according to
customary procedures.

R01 applications submitted in response to this RFA may not request a total
project period of more than 5 years.  A maximum of 3 years can be requested for
foreign awards.  In general, the maximum budget request for R01 applications
should be limited for $160,000 in direct costs for the first budget year. 
Requests for support that exceeds that amount will require a thorough
justification, and in no case will a request exceeding $250,00 in direct costs
for the first budget year be allowed under this solicitation.

R21 (Exploratory Research Grant) applications may not exceed 3 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 may be used by new investigators and experienced investigators
to develop pilot and feasibility studies for new and innovative approaches to
clinical aspects of IC, especially exploration of therapeutic interventions and
biomarkers of disease.  R21 applications generally are expected to have little
preliminary data and are reviewed based on the development of hypotheses and
supporting literature.

All applications must budget for travel to an annual meeting at the NIH or in the
Washington, D.C. area.

The anticipated award date for all grants is September 30, 1999.

FUNDS AVAILABLE

A total of $2.0 million in total costs will be committed by the NIDDK in fiscal
year 1999 to fund applications of high scientific merit submitted under this RFA. 
This funding level is dependent upon the receipt of a sufficient number of
applications of high scientific merit.

It is anticipated that 10 to 12 awards will be made, depending on the mix of R01
and R21 grants awarded.  Although this program is provided for in NIDDK's
financial plan, the award of grants under this RFA is also contingent on the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

The painful bladder syndromes are a group of disorders manifest predominantly by
pelvic pain and bladder instability, usually urinary urgency and frequency.  IC
is a major disorder in this group of syndromes.  There is no scientifically
demonstrated etiology for these disorders, and the pathological and
pathophysiological features of bladder tissue from patients are variable and have
not been well correlated with symptoms.  Although the scientific literature on
IC is increasing, many theories about pathological changes in the bladder still
have not been rigorously tested.  One impediment to understanding IC is the lack
of basic knowledge about the pathology of the urinary bladder.

Painful bladder syndromes are primarily described clinically and can be roughly
divided into three categories based on the clinical course: 1) people whose
symptoms subside spontaneously with relatively infrequent, self-limited flares;
2) people with chronic symptoms but steady objective findings: 3) people with
chronic symptoms and a progressive disorder that results in an "end-stage"
physically and functionally smaller bladder.  Both stress and urge urinary
incontinence may be present to varying degrees, especially in people in groups
2 and 3.  These three categories may represent separate diseases or different
manifestations of the same underlying problem.  The development of reliable serum
or urine markers of inciting pathology and/or correlates of disease severity,
pathology, and prognosis would represent significant progress in understanding
and treating painful bladder syndromes.

Well-designed clinical studies of painful bladder syndromes may also provide
information on which to base studies of etiology and pathobiology.

Scientific Objectives

The following examples of research topics are just a few that could be considered
for support under this RFA.  We anticipate that many applications ultimately
funded under this RFA may, in fact, propose topics that are not listed:

o  To increase the molecular, cellular, and genetic understanding of the
relationship between the bladder epithelium, it's underlying tissues, its
innervation, and the pelvic floor.

o  To develop methods to identify and separate bladder cells from the urine,
utilizing fluorescent activated cell sorting.

o  To develop biomarkers of disease in women with painful bladder syndromes and
correlate markers with symptoms and prognosis.

o  To define the relationship between pathological findings in human tissue and
mechanisms of disease pathogenesis.

o  To test innovative hypotheses about the etiology and pathogenesis of painful
bladder syndromes.

o  To characterize the molecular and cellular effects of therapeutic agents on
bladder tissue and correlate with symptoms.

Program Objectives:

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

o  To increase the diversity of expertise in clinical and allied disciplines
applied to painful bladder syndromes.

o  To verify the existing knowledge about the pathology and pathogenesis of
painful bladder syndromes by developing and conducting rigorous clinical and
basic science studies utilizing human subjects and tissues.

o  To develop innovative genetic and bioengineering approaches to studies on the
bladder and the painful bladder syndromes.

Research Scope:

Clinical research is defined as studies involving people with painful bladder
syndrome and, if necessary, appropriate control subjects.

Basic research studies may involve tissue from human subjects, either with
disease or controls, or animal models or tissues.

Clinical research on biomarkers of disease and clinical interventions are limited
to people with documented IC or chronic pelvic pain and to normal control
subjects.  Animal models are not valid for these studies.

SPECIAL REQUIREMENTS

Clinical research studies on IC must use the NIDDK Research Criteria for IC for
inclusion of patients.  The scope of clinical patients may exceed the NIDDK
criteria, but rationale and diagnostic criteria must be well defined and
justified.

All animal models used for basic research studies must delineate the limitations
of the model.

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 al 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 subjects of the purpose of the research.  This new
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 "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:
http://grants.nih.gov/grants/guide/notice-files/not94-105.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the 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://grants.nih.gov/grants/guide/notice-files/not98-014.html

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 March 14, 1999,  a letter of
intent that includes a descriptive title of the proposed research; the name,
address, and the telephone number of the Principal Investigator; the identities
of other key personnel and participating institutions; and the number and title
of this RFA.  Although a letter of intent is not required, is not binding, and
does not enter into the review of a subsequent application, the information 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) 549-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used to apply
for grants under this RFA. These forms are available at most institutional
offices of sponsored research and the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone: (301) 435-0714, Email:
GrantsInfo@nih.gov

Special Instruction For R01 Submissions þ Modular Grants

All R01 grants will be awarded as modular grants.  The modular grant concept
established specific modules (increments) in which direct costs may be requested
and a maximum level for requested direct costs.  Only limited budgetary
information is required in the application; a detailed budget need not be
provided.

Sample budgets and justification pages will be provided upon request from Ms.
Trude Hilliard at the address listed under INQUIRIES or following submission of
a letter of intent.

Budget 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:

o Face Page:  As a reminder, Item 7 should be completed to indicate Modular
Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus
F&A costs).

O Detailed Budget For The Initial Budget Period:  Do not complete Form Page 4 of
the PHS 398 (rev 4/98).  It is not required nor will it be accepted at the time
of application.

O Budget For The Entire Period Of Support:  Do not complete the categorical
budget on Form page 5 of the PHS 398 (rev. 4/98).  Only the requested total
direct costs line for each year must be completed based on the number of $25,000,
modules being requested.  Applicants may not request a change in the amount of
each module.  A maximum of TEN MODULES ($250,000 direct costs) per year may be
requested and each applicant may request up to FIVE years of support for R01
applications, as specified in the MECHANISM OF SUPPORT section of this RFA. 
Direct cost budgets of modules requested will remain constant throughout the life
of the project ( i.e., the same number of modules requested for all budget
periods).  Any necessary escalation should be considered when determining the
number of modules to be requested.  However, in the event that the number of
modules to be requested must change in any future year due to the nature of the
research proposed, appropriate justification must be provided.  Total Direct
Costs of the Entire Proposed Project Period should be shown in the box provided.

O Budget Justification:  Budget justifications should be provided under
"Justifications" on Form Page 5 of the PHS 398

-  List the names, role on the project and proposed percent effort for all
project personnel (salaried and unsalaried) and provide a narrative justification
for each person based on his/her role on the project.  UNDER THE JUSTIFICATION
FOR THE PRINCIPAL INVESTIGATOR, INDICATE IF YOU ARE A NEW INVESTIGATOR (i.e., AN
INVESTIGATOR WITHOUT PRIOR R29 OR R01 SUPPORT).

-  Identify all consultants by name and organizational affiliation and describe
the services to be performed

-  Provide a general justification for individual categories (equipment,
supplies, etc.) required to complete the work proposed.  More detailed
justifications should be provided for high cost items.  Any large one-item
purchases, such as large equipment requests, must be accommodated within these
limits.  No specific costs for items or categories should be shown.

o  Consortium/Contractual Costs:  If collaborations or subcontracts are involved
that require transfer from the grantee to other institutions, it is necessary to
establish formal subcontract agreements with each collaborating institution.  A
letter of intent from each collaborating institution should be submitted with the
application.  Only the percentage of the consortium/contractual TOTAL COSTS
(direct and indirect) relative to the total DIRECT COSTS of the overall project
needs to be stated at this time.  The following example should be used to
indicate the percentage cost of the consortium, "The consortium agreement
represents 27% of overall $175,000 direct costs requested in the first year." 
A budget justification for the consortium should be provided as described in the
"Budget Justification" section above (no Form Page 5 required for the
consortium). Please indicate whether the consortium will be in place for the
entire project period and identify any future year changes in the percentage
relative to the parent grant.

If there is a possibility for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the consortium. 
Please note that total subcontract funds are added to the parent grant budget,
the total direct cost amount must be indicated in the number of $25,000 modules
requested.

o  Biographical Sketch:  A biographical sketch is required for all key personnel,
following the modified instruction below.  Do not exceed the two-page limit for
each person.

-  Complete the education block at the top of the form page

-  List current position(s) and those previous positions directly relevant to the
application;

-  List selected peer-reviewed publications directly relevant to the proposed
project, with full citation;

-  The applicant has the option to provide information on research projects
completed and/or research grants participated in during the last five years that
are relevant to the proposed project.

O Other Support:  Do not complete the "Other Support" pages (Form Page 7).
Selected other support information relevant to the proposed research may be
included in the Biographical Sketch as indicated above.  Complete Other support
information will be requested by Institute Staff if there is a possibility for
an award.

o  Checklist:  No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by Institute Staff if there
is a possibility for an award.

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.

R01 applications not conforming to these guidelines will be considered
unresponsive to the RFA and will be returned without further review.

THE MODULAR GRANT APPLICATION DOES NOT APPLY TO R21 GRANT APPLICATIONS (follow
instructions the PHS Form 398 rev. 4/98).

The RFA label available in the PHS 398 (rev. 4/98) 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, plus three 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)

At the 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 April 12, 1999. 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 is 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.

REVIEW CONSIDERATIONS

Applications will be reviewed for completeness by the CSR and responsiveness by
NIDDK.  Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by the NIDDK in accordance with the
review criteria stated below. 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 the applications under review, 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

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
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.

o  Significance: Does this study address an important problem? If the aims of the
applications 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 methods? 
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  Reasonableness of the proposed research budget and duration in relation to the
proposed research.

o  Adequacy of plans to include both genders, minorities and their subgroups, and
children as appropriate as appropriate for the scientific goals of the research. 
Plans for the recruitment and retention of subjects when necessary will also be
evaluated.

o  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

The following will be considered in making the funding decisions:

o  Quality of the proposed project as determined by peer review
o  Uniqueness of proposed studies
o  Availability of funds
o  Program priorities

INQUIRIES

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

Inquiries regarding programmatic issues should be directed to:

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

Inquiries regarding fiscal, budget and administrative matters, including the
modular grant preparation, should 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

Letter of Intent Receipt Date:  March 14, 1999
Application Receipt Date:       April 12, 1999
Initial Review:                 June-July 1999
Advisory Council Review:        September 1999
Anticipated Date of Award:      September 30, 1999

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 Regulation 42 CFR
52 and 45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health System Agency review.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of tobacco products.  In addition, Public
Law 103-277, 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.



Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.


Y> Y>