Full Text DK-94-022

PATHOPHYSIOLOGY OF ALCOHOL AND DRUG-INDUCED PANCREATITIS

NIH GUIDE, Volume 23, Number 22, June 10, 1994

RFA:  DK-94-022

P.T. 34

Keywords: 
  Digestive Diseases & Disorders 
  Pathophysiology 
  Alcohol/Alcoholism 
  Adverse Effects 


National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Alcohol Abuse and Alcoholism

Letter of Intent Receipt Date:  September 22, 1994
Application Receipt Date:  October 20, 1994

PURPOSE

The Division of Digestive Diseases and Nutrition of the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and
the National Institute on Alcohol Abuse and Alcoholism (NIAAA) wish
to encourage applications on the above subject.  This includes basic
and clinical studies into the pathophysiology of alcohol and
drug-induced 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 Request
for Applications (RFA), Pathophysiology of Alcohol and Drug-Induced
Pancreatitis, 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
Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Minority individuals
and women are encouraged to submit as principal investigators.

MECHANISM OF SUPPORT

Support of this program will be through the NIH research project
grant (R01) and the FIRST (R29) award.  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  Awards will be administered under 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.  FIRST awards are for five years.
The total requested project period for each application for an R01
grant submitted in response to this RFA may not exceed five years.
(three years will be requested for foreign awards).  The earliest
possible award date will be July 1, 1995.

FUNDS AVAILABLE

For FY 1995, $1.5 million will be committed to fund applications
submitted in response to this RFA.  It is anticipated that five to
eight awards will be made; one to two by NIAAA and four to six by
NIDDK.  However, this funding level is dependent upon the receipt of
a sufficient number of applications of high scientific merit.
Applicants must limit their R01 requests to not more than $150,000 in
direct costs for the initial budget period.  FIRST (R29) award
applications must adhere to the R29 guidelines for budget and period
of award.  Although this program is provided for in the financial
plans of the NIDDK and NIAAA, the award of grants pursuant to this
RFA is also contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

The overall goal of this initiative is to encourage experienced and
new investigators to pursue basic and clinical investigations into
the pathophysiology of alcohol and drug-induced pancreatitis.
Although there has been considerable research into the physiology of
the pancreatic acinar cell as well as the normal function and
diseases of the pancreatic duct cell, continued research efforts need
to be focused on pancreatitis with a particular emphasis on alcohol
and other medications and toxins as etiological factors.  At present,
it is still unclear how alcohol abuse or drugs induce the
auto-destructive tissue necrosis observed in acute pancreatitis.  It
has been postulated that the initial insult produces damage to the
acinar cell or promotes ductal obstruction, thereby releasing
auto-destructive enzymes and initiating the pancreatic pathological
sequelae.  More recent investigations have suggested that inhibition
of mitochondrial function by drugs may lead to cell injury and
release of destructive enzymes.  A number of drugs are considered to
cause pancreatitis.  They include thiazide diuretics, azathioprine,
6- mercaptopurine, dideoxyinosine, 1-2' deoxy-2' fluoro-1-B-D
arabinofuranosyl-5- iodo-uracil (FIAU) and valproate.  Elevated
estrogen levels and the administration of corticosteroids or
estrogens aggravate hypertriglyceridemia, which can precipitate
pancreatitis.

Chronic pancreatitis, characterized by recurrent or persistent pain,
is characterized by focal inflammation and fibrosis.  Pancreatic
ducts may be dilated and obstructed by intraductal plugs.  Exocrine
or endocrine insufficiency may also be observed.  Alcohol consumption
is a complicating factor in at least half of the reported cases of
chronic pancreatitis.  Whether or not alcohol injures pancreatic
tissue directly through intestinal hormones (cholecystokinin and
secretin) and or through mechanisms involving pancreatic enzymes
needs clarification.

Cytokines and/or growth factors, such as tumor necrosis factor, may
be involved in the pathogenesis of alcohol-related pancreatitis since
this factor is elevated in bile-induced pancreatitis in rats and in
patients with alcoholic hepatitis.  In addition, oxygen-derived free
radicals have been implicated in the development of pancreatitis in
mice.  Whether or not alcohol-induced free radical development is
causally related to pancreatitis needs investigation.

Increased pancreatic synthesis of fatty acid ethyl esters (FAEEs) is
associated with chronic alcohol feeding.  FAEEs have also been shown
to increase the fragility of isolated pancreatic lysosomes thereby
releasing destructive lysosomal enzymes.  Thus, mechanisms that
elucidate FAEEs' contribution to the development of alcohol-related
pancreatitis are warranted.

STUDY POPULATIONS

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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

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 9, 1994 (FR 59 11146-11151) and reprinted
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 September 22, 1994, 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 the subsequent application, the
information that it contains is helpful in planning for the review of
applications.  It allows NIDDK and NIAAA 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:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083
FAX:  (301) 594-7503

APPLICATION PROCEDURES

The research grant application form PHS-398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 710-0267.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page.  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 2a of the face page of
the application form and check the YES box.

FIRST Award applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST Award applications submitted without the required number of
reference letters will be considered incomplete and will be returned
without review.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by October 20, 1994.  If an application
is received after that date, it will be returned to the applicant.
The Division of Research Grants (DRG) 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.  However, it is allowable to submit the same project as
both an R01 and as a component project of a program project.  The DRG
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.  Such
applications must include an introduction addressing the previous
critique and also be responsive to this RFA.

REVIEW CONSIDERATIONS

Upon receipt, applications will be initially reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIDDK and NIAAA staff function.  If the application is not
responsive to the RFA, NIDDK or NIAAA staff will contact the
applicant to determine whether it should be returned to the
applicant, or held until the next regular receipt date and reviewed
in competition with all other applications.

Applications that are complete and responsive will be evaluated for
scientific and technical merit by an appropriate peer review group
convened by the NIDDK in accordance with the review criteria stated
below.  As part of the initial merit review, a process (triage) may
be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response
to the RFA.  Applications judged to be competitive will be discussed
and be assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.  Following this review, the
applications will be given a secondary review by the NIDDK or NIAAA
Advisory Council unless not recommended for further consideration by
the initial review group.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific/technical merit criteria specific to the objectives of
the RFA;

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff particularly, but not exclusively, in the area
of the proposed research;

o  availability of resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed-means for protecting against or minimizing such effects; and

o  if the application is submitted from an institution outside the
United States, uniqueness of research such that it can only be
performed outside of the United States.

AWARD CRITERIA

Funding decisions will be made based on the initial review group and
national advisory council recommendations, program relevance, and
availability of funds.

INQUIRIES

Written and telephone 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:

Thomas F. Kresina, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A17
Bethesda, MD  20892
Telephone:  (301) 594-7578

Vishnudutt Purohit, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Rockville, MD  20892-7003
Telephone:  (301) 443-4224

Inquiries regarding fiscal matters may be directed to:

Mrs. Thelma Jones
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 594-7543

Schedule

Letter of Intent Receipt Date:  September 22,1994
Application Receipt Date:       October 20,1994
Initial Review:                 February-March 1995
Second Level Review:            May-June 1995
Anticipated Date of Award:      July 1, 1995

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 Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

Return to RFAs Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.