INTEGRATIVE APPROACHES TO THE STUDY OF MOTILITY OF THE GASTROINTESTINAL TRACT

Release Date:  January 20, 1999

RFA:  DK-99-004

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
Office of Research on Women's Health
American Digestive Health Foundation

Letter of Intent Receipt Date: February 24,1999
Application Receipt Date: March 24, 1999

PURPOSE

The National Institute of Diabetes Digestive and Kidney Diseases (NIDDK), through
its Division of Digestive Diseases and Nutrition, and the American Digestive
Health Foundation (ADHF) invite experienced and new investigators to submit
research grant applications to pursue basic and applied investigations into
motility disorders of the gastrointestinal tract.  The intent of this Request for
Applications (RFA) is to (1) encourage interaction between basic scientists and
clinical investigators with special interest in motility-related disorders of the
alimentary canal; (2) encourage collaborative interactions among
gastroenterologists, urologists, gynecologists and neuroscientists; and (3)
attract new and established investigators to the field of gastrointestinal
motility.  In recognizing the need for research in this field, the Office of
Research on Women's Health, in collaboration with the NIDDK, is interested in
studies that address sex/gender differences in motility-related disorders,
especially involving those disorders that disproportionately affect women.

The overall scientific goals of this initiative are to enhance the understanding
of: (1) the genetic, molecular, cellular, and physiological changes that occur
in the bowel wall, central brain nuclei, and peripheral autonomic ganglia
innervating the gastrointestinal tract in persons and animal models with
motility-related disorders; (2) the biochemical coding of stress-related
alterations of gastrointestinal motility; (3) physiological and cognitive
influences on the etiology and course of functional gastrointestinal motility
disorders; (4) food-related motor disturbances of the gastrointestinal tract; and
(5) the ontogeny at the genetic, molecular, and cellular levels of lifelong
motility disorders.

HEALTHY PEOPLE 2000

The NIH 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, Integrative Approaches to the Study of Motility of the
Gastrointestinal Tract, is related to the priority area of diabetes and chronic
disabling conditions. 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

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 or 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 NIH research project grant (R01)
award and the Exploratory/Developmental (R21) grant program.  The R21 grant is
a means of supporting a pilot or feasibility project, providing support for a new
investigator or an established investigator who is embarking on a new direction. 
The R21 mechanism is designed to support research that is innovative but that may
lack an historical basis or preliminary data.  These grants are non-renewable
awards that are meant to lead to a full-scale R01 application.

Responsibility for the planning, direction, and execution of the proposed project
will be solely that of the applicant.  Awards will be administered under the 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.

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.  The total requested
project period may not exceed 5 years for R01 applications or 2 years for R21
applications.  The maximum dollar request is limited to $200,000 in direct costs
for the initial budget period for R01s or $100,000 in direct costs for R21s.  The
anticipated award date is September 30, 1999.

FUNDS AVAILABLE

For FY 2000, $2.5 million will be committed to fund applications submitted in
response to the RFA.  It is anticipated that 12 to 15 awards will be made;
however, this funding level is dependent upon the receipt of a sufficient number
of applications of high scientific merit.  Although this program is provided for
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

Motility-related disorders of the gastrointestinal tract present a major health
problem for the citizens of the United States.  It has been estimated that nearly
5 million Americans report having irritable bowel syndrome (with a female
predominance of 2.5 females to 1 male); fecal incontinence affects approximately
7 percent of the U.S. population, particularly the elderly, and constipation
affects 3 percent; 14 percent of the US population reports reflux symptoms on a
weekly basis; 20 percent of diabetic patients have gastroparesis; an unknown
number of infants and children have functional bowel disorder; and an
undetermined number of women are affected with pelvic floor dysfunction.

Sixty percent of patients with irritable bowel syndrome have several food
intolerances expressed through changes in gastrointestinal motility.  A large
number of female patients with the irritable bowel syndrome also have urinary
bladder irritability, pelvic pain, and evidence of pelvic floor or external
sphincter disorders.  Pelvic floor disorders may be a common focus for lower
gastrointestinal, urologic and gynecologic disorders.  The genetic basis and the
molecular and cellular etiology of gastrointestinal motility disorders are not
known.  The advent of transgenic and knockout technology in mice and the
development of new methods for studying the neurobiology and motility of the
alimentary canal present new opportunities for increasing the understanding of
the mechanisms underlying motility of the alimentary canal in health and disease. 
Ontogenic work at the molecular and cellular levels as well as at the functional
in vivo level provides opportunities for understanding a number of lifelong
motility disorders.

This RFA is designed to support basic and clinical research on integrative
approaches to the study of the motility of the gastrointestinal tract so that
effective diagnostic modalities and treatment interventions can be developed. 
Relevant topics of research include, but are not limited to the following:

o  Identify and characterize factors which direct the formation and maintenance
of synaptic connections in the enteric nervous system and how neurons of the
enteric nervous system function as a unit using functional, morphological, and
imaging approaches.

o  Identify the molecular genetics guiding the migration, sacral proliferation,
survival, and differentiation of vagal and sacral crest cells.

o  Identify the genetic, molecular and cellular mechanisms for formation of the
enteric smooth muscle coats and their description in myopathic diseases.

o  Identify and characterize factors that regulate the development and plasticity
of intestinal cells.

o  Study the effects of gestational hormones on development of enteric nerves.

Molecular Biology and Ion Channels

o  Identify mechanisms of receptor regulation at the transcriptional and post-
transcriptional levels in normal tissue and the changes that occur in motility
disorders of the alimentary canal.

o  Molecular identification and the functional description of the proteins
regulating ionic conductances and intercellular and intracellular signaling
pathways modulating ionic conductance in smooth muscle, enteric and peripheral
autonomic neurons, and intestinal cells.

o  Identification of the contractile protein isoforms that are involved in phasic
versus tonic contractions in gastrointestinal smooth muscles.

Neuroimmune Interactions

o  Characterize the population and identity of inflammatory cells resident in the
normal bowel, and the trafficking (migration) of inflammatory cells in the gut
wall.

o  Characterize interactions between the immune system and the neuromuscular
apparatus of the bowel wall including intrinsic and extrinsic nerves and the
intestinal cell network in post infection states (IBD, gastroparesis) and
acquired pseudo-obstruction.

o  Identify the molecular, biochemical and physiological processes involved in
neurogenic modulation of inflammation, inflammatory pain, and the mechanisms of
development of post-inflammatory visceral hyperalgesia.

o  Characterize pathways mediating motility changes seen in acute and chronic
intestinal inflammation.

o  Identify the role of neuroendocrine responses in susceptibility to the
inflammatory component of motility disorders.

o  Explore and exploit animal models and paradigms of enteric infections that
lead to dysmotility.

o  Examine the role of viruses as initiators of motility disorders,

o  Examine the role of oxidative stress and free radical formation in motility
disorders.

Functional Genomics, Translational Research

o  Identify and characterize the role of interstitial cells in motility disorders
such as achalasia, esophageal reflux, pseudo-obstruction, diarrhea and
constipation.

o  Identify neural mechanisms coordinating motility and secretion.

o  Identify brain regions mediating peripheral autonomic responses to visceral
stimuli arising in the gastrointestinal tract.

o  Elucidate the neural pathology of central and enteric neural circuitry and the
pathology of myogenic intracellular signal transduction in the bowel wall of
patients with diabetic gastroparesis, gut inflammation, pseudo-obstruction,
constipation, and reflux disease of the esophagus.

o  Develop better physiological methods and markers for defining the
pathophysiology of functional gastrointestinal disorders, constipation, fecal
incontinence, and pelvic floor dysfunction thereby leading to better rational
therapy in these disorders.

o  Validate methods by which human motility disorders can be documented in
clinical practice.

o  Validate diagnostic tests for patients with functional gastrointestinal
disorders, constipation, fecal incontinence and pelvic floor dysfunction by
describing in large stratified samples, normal physiological mechanisms and the
pathophysiologic findings in these patients.

o  Identify and characterize genetic markers which identify disorders of motility
of the gastrointestinal tract.

o  Conduct epidemiologic and long-term outcome research of functional
gastrointestinal disorders, constipation, fecal incontinence, and disorders of
pelvic floor function with the objective of identifying a marker or markers that
may predict disease behavior.  These studies may evaluate outcomes related to
pharmacological, surgical or behavioral interventions.

o  Compare the efficacy of biofeedback and other modalities to medical and
surgical management of fecal incontinence and constipation in multicenter
randomized, placebo-controlled studies.

o  Develop sophisticated intraluminal sensors based on miniaturization and
microprocessor technology and non-invasive sensing technologies to provide more
reliable probes for monitoring/measuring motility in vivo in the normal human
subject and patient, in normal and genetically modified mice, and in other animal
models of motility disorders.

Functional Bowel Disease

o  Map the central representation of autonomic and gut visceral afferent nerve
activity using electrophysiological and pharmacological methods in laboratory
animals and advanced imaging techniques (MRI, PET) in patients with hyperalgesia
and in patients with well-characterized, motility disorders of the alimentary
canal.

o  Study the pharmacology and electrophysiology of visceral hypersensitivity
including the role of gestational hormones.

o  Identify physiological markers (for example, visceral hypersensitivity
testing, regional cerebral blood flow using MRI, brain, imaging using Pet) and
psychological markers (as for example, presence of depression or somatization
disorders) for functional gastrointestinal disorders.

o  Establish clinical trials comparing the efficacy of pharmacological and non-
pharmacological approaches to the treatment of functional gastrointestinal
disorders, constipation, fecal incontinence and pelvic floor dysfunction, and
develop tools to assess outcomes of treatment.

o  Characterize the anatomic and physiologic mechanisms that constitute or
contribute to pelvic floor dysfunction.

o  Identify the incidence of pelvic floor dysfunction in patients with
constipation and difficult evacuation.

o  Identify the mechanisms involved in colonic inertia vs outlet dysfunction
associated constipation.

o  Provide a better understanding of sensory functions at the level of detection
in the digestive tract, processing of sensory information by the central nervous
system, and psychosocial aspects of sensory perception in relation to functional
disorders of the gastrointestinal tract.

o  Develop a better understanding of the interaction between food (nutrients) and
other ingested substances and motility/transit of the gut.

Motor Disorders in Infants and children

o  Conduct prospective integrative and cross-disciplinary studies of populations
known to be at risk for the development of functional gastrointestinal disorders,
including children of parents who have functional gastrointestinal disorders,
patients with a history of sexual or physical abuse, and patients with an acute
episode of gastroenteritis.

o  Identify the physiological basis and the underlying cellular and molecular
mechanisms for motility disorders unique to infants and children.

o  Study the development of normal electrical activity and normal patterns of
motility in prenatal, neonates, children, and adolescents incorporating in vivo
and in vitro approaches.

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
rational 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, 19994
(FR 59 14508-14513), and in the NIH Guide For Grants and Contracts, Volume 22,
Number 23, Number 11, March 18, 1994.

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:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 24, 1999, 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 is being submitted.

Although a letter of intent is not required, is not binding, and does not enter
into the review of subsequent applications, the information that it contains is
helpful in planning for the review of applications.  It allows NIH staff to
estimate the potential review workload and to avoid possible conflict of interest
in the review.

The letter of intent is to be sent to:

Frank A. Hamilton, M.D., MPH
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN12B, MSC 6600
Bethesda, MD  20892
Telephone:  (301) 594-8877
FAX:  (301) 480-8300

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) 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:
GrantsInfo@nih.gov.

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, including the
Checklist, plus 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)

Applications must be received by March 24, 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 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 will be assigned on the basis of established PHS referral
guidelines.  Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer review
procedures.  As part of the initial merit review, all applications will receive
a written critique and undergo processing 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

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.

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?

Approach: Are the conceptual framework, design, methods, and analyzed adequately
developed, well-integrated, an appropriate to the aims of the project?  Does the
applicant acknowledge potential problem areas and consider alternative tactics?

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?

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)?

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?

Appropriateness of the proposed budget and duration of project period in relation
to the proposed research.

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.

The initial review group will also examine the provisions for the protection of
human and animal subjects, and the safety of the research environment.

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 anticipated date of award is September 30, 1999.  Applications will compete
for available funds with all other recommended applications submitted in response
to this RFA. The following will be considered in making funding decisions:
quality of the proposed projects as determined by peer review, availability of
funds, and program balance and scientific interrelationships among the proposed
projects.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Frank A. Hamilton, M.D., MPH
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN12B, MSC 6600
Bethesda, MD  20892
Telephone:  (301) 594-8877
FAX:  (301) 480-8300
Email:  hamiltonf@extra.niddk.nih.gov

Michael Ken May, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN18J, MSC 6600
Bethesda, MD  20892
Telephone:  (301) 594-8884
FAX:  (301) 480-8300
Email:  mayk@extra.niddk.nih.gov

Tommie Sue Tralka
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8879
FAX:  (301) 480-8300
Email:  tralkat@extra.niddk.nih.gov

Inquiries regarding fiscal and administrative matters to:

George Tucker, MBA
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building 45, Room 6AS49E
Bethesda, MD  20892
Telephone:  (301) 594-8853
FAX:  (301) 480-3504
Email:  tuckerg@extra.niddk.nih.gov

Schedule

Letter of Intent Receipt Date:  February 24, 1999
Application Receipt Date:       March 24, 1999
Initial Review:                 June-July 1999
Second Level 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.
93.848.  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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