MOLECULAR AND GENETIC MECHANISMS IN PANCREATITIS

Release Date: January 14, 1999

PA NUMBER:  PA-99-040

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

The Division of Digestive Diseases and Nutrition and the Division of Diabetes,
Endocrinology and Metabolic Diseases of the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) wish to encourage experienced and new
investigators to pursue basic and clinical investigations into the molecular
biology and molecular genetics of acute and chronic pancreatitis as well as
pancreatic insufficiency associated with cystic fibrosis.  Studies are sought to
expand the recently reported observations that some patients with pancreatitis
have mutations in CFTR, the gene that causes cystic fibrosis.  Coupled with the
recently identified gene for hereditary pancreatitis and a possible association
of pancreatitis with mutations in the alpha-1-antitrypsin gene, further studies
are warranted on the molecular and genetic mechanisms of acute and chronic
pancreatitis.  Basic studies include the molecular regulation or biological
mechanisms of mutated genes in the generation of pancreatitis as well as the
generation of animal models of pancreatitis and, particularly, organ-specific
transgenic or knock-out mice that exhibit acute or chronic pancreatic
abnormalities.

Clinical and epidemiological studies are also sought that increase our knowledge
of the risk factors, means of detection and diagnosis, natural history and
prognosis, prevention and treatment of pancreatitis.  These studies could utilize
the recent advances that identify mutated genetic loci in patients with
pancreatitis.

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 Program Announcement (PA), MOLECULAR
AND GENETIC MECHANISMS IN PANCREATITIS, is related to one or more of the priority
areas.  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 and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project grant
(R01) award mechanism as well as the Exploratory/Developmental Grant (R21) award
mechanism.  The total project period for a research project grant (R01)
application submitted in response to this PA may not exceed 5 years.  The
Exploratory/Developmental Grant (R21) award provides funds for exploratory
research projects (maximum $100,000 per year for two years).  Applications for
the R21 Award should stress the innovative and exploratory nature of the proposed
research.  Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.

RESEARCH OBJECTIVES

Pancreatitis is a syndrome that is characterized by recurrent attacks of pain
associated with inflammation and damage to the pancreas.  Relapsing or chronic
pancreatitis can lead to exocrine and endocrine pancreatic insufficiency.  Major
causes of pancreatitis are alcohol and cholelithiasis.  However, a large
percentage of cases are idiopathic, in that no causative agent can be found
despite extensive investigation.  Recently, a hereditary component has been
elucidated with the identification and cloning of a "hereditary pancreatitis"
gene.  Mutations in the pancreatic trypsinogen gene can cause a loss of auto-
regulation of the pancreatic digestive enzymes and subsequent auto-digestion of
the pancreas by the potent proteases that the organ produces.

Pancreatic insufficiency is also seen in most patients with cystic fibrosis.
These patients have progressive pancreatic damage as a result of ductal
inspissation that leads to early clinical manifestations of maldigestion due to
pancreatic insufficiency.  Individuals with more severe forms of the disease who
have pancreatic insufficiency have a shorter median survival of 29 years compared
to cystic fibrosis patients with milder forms of the disease with pancreatic
sufficiency (56 years median survival).  The discovery of the cystic fibrosis
transmembrane conductance regulator (CFTR) gene has resulted in significant
progress in the understanding of the wide spectrum of abnormalities comprising
cystic fibrosis.  More than 800 putative mutations of the CFTR gene have been
identified and attempts have been made to elucidate the relationship between
genotype and the phenotype of the disease including the pancreatic
manifestations.  CF patients with pancreatic insufficiency generally have two
alleles associated with severe abnormalities.  Mutations associated with severe
disease account for approximately 92% of known mutant CFTR chromosomes, and thus
approximately 84% of patients will have two alleles associated with severe
disease with pancreatic insufficiency.

Recent studies have reported that 6-37% of patients with idiopathic pancreatitis
have a CFTR mutation on at least one chromosome.  Some individuals with
"idiopathic" pancreatitis were identified with two mutant CFTR alleles but did
not have lung disease of typical cystic fibrosis.  Genetic testing of patients
with pancreatitis has identified individuals with other genetic abnormalities,
including an abnormal alpha-1-antitrypsin phenotype with low serum protein level. 
Thus, genetic screening of patients with pancreatitis has resulted in identifying
numerous abnormal genes possibly related to the pancreatic injury.  The alleles
when homozygous are associated with severe pancreatic disease.  Thus, these
studies have resulted in the possibility of a gene dosage effect in the etiology
of some forms of idiopathic pancreatitis.

This PA requests both basic and clinical studies that address the identification
of genetic factors predisposing individuals to pancreatitis.  Such studies would
include but are not limited to research specific aims that promote:

o  Genetic screening studies that identify gene mutations in candidate genes or
their regulatory elements associated with pancreatic structural or functional
abnormalities;

o  The identification of biologic or molecular mechanisms of pancreatic injury
associated with the identification of mutant alleles;

o  The generation of novel animal models of pancreatitis or abnormal pancreatic
function by expression of mutant genes associated with pancreatic disease; and

o  Identification of other genetic and environmental factors that influence the
development and course of pancreatitis in genetically susceptible individuals.

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 have been 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 the following URL address: 
http://www.nih.gov/grants/guide/notice-files/not94-105.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 also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated in
the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
GrantsInfo@nih.gov.

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct costs
for any year are advised that he or she must contact the Institute or Center (IC)
program staff before submitting the application, i.e, as plans for the study are
being developed.  Furthermore, the application must obtain agreement from the IC
staff that the IC will accept the application for consideration for award. 
Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute or Center who agreed to accept
assignment of the application.  This policy requires an applicant to obtain
agreement for acceptance of both any such application and any such subsequent
amendment.  Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at
http://www.nih.gov/grants/guide/notice-files/not98-030.html

The title and number of the program announcement must be typed on line 2 of the
face page of the application form, and the YES box must be 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 PHS referral
guidelines.  Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard NIH peer review procedures.  As part of the initial merit review, all
applications will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit, generally the top
half of applications under review, will be discussed, assigned a priority score,
and receive a second level review by the appropriate national advisory council
or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In the
written comments reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.  Note that the application does not need to be
strong in all categories to be judged likely to have major scientific impact and
thus deserve a high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is essential
to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

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

(3) Innovation:  Does the project employ novel concepts, approaches or method?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

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

o  The reasonableness of the proposed budget and duration in relation to the
proposed research

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

AWARD CRITERIA

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

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Thomas F. Kresina, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AN-12A
Bethesda, MD  20892
Telephone:  (301) 594-8871
FAX:  (310) 480-8300
Email:  tk13v@nih.gov

Catherine McKeon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN-18B
Bethesda, MD  20892-6600
Telephone: (301) 594-8810
FAX:  (301) 480-3503
Email:  Catherine_McKeon@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Donna A. Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 6AS-49K
Bethesda, MD  20892
Telephone:  (301) 594-8848
FAX:  (301) 480-3504
Email:  hugginsd@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.848 and 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, and portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.

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