RELEASE DATE: October 08, 2003

PA NUMBER:  PA-04-005

November 20, 2006 - The R01 portion of this funding opportunity has been replaced by 
PA-07-067, which now uses the electronic SF424 (R&R) application for February 5, 2007 
submission dates and beyond.

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. Parent 
R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been 
issued for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter. Applications relating to R33 and R34 activities 
must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for All R01 Applications: October 15, 2006 unless 

Department of Health and Human Services (DHHS)
National Institutes of Health (NIH)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Diabetes and Digestive and Kidney Diseases 
National Institute on Drug Abuse (NIDA) 



o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The National Institute on Alcohol Abuse and Alcoholism (NIAAA), 
National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), and National Institute on Drug Abuse (NIDA) are seeking 
research grant applications that will investigate the underlying 
molecular, biochemical, and cellular mechanisms by which long-term 
alcohol ingestion leads to the development of pancreatitis. Research is 
also encouraged to understand the role of various predisposing factors, 
including substance abuse, that make the pancreas susceptible to 
alcoholic injury. Understanding the mechanisms as well as the role of 
predisposing factors may help in developing strategies for the 
prevention or treatment of the disease. 


Long-term heavy alcohol consumption is associated with both acute and 
chronic pancreatitis. Acute pancreatitis is characterized by pain, 
edema, hemorrhage, acinar cell vacuolation, necrosis and increased 
serum levels of amylase and lipase. Chronic pancreatitis is 
characterized by features of acute pancreatitis superimposed on a 
background of chronic changes that include fibrosis, inflammation, some 
level of calcification, and loss of exocrine tissue. Progression of 
pancreatitis may lead to multiple co-morbidities including 
maldigestion, diabetes, and pancreatic cancer. A recent advance in our 
understanding of pancreatitis is the development of animal models of 
alcoholic pancreatitis using co-factors such as cholecystokinin-8 (CCK-
8), unsaturated fat, and viral infection. However, further refinement 
is required in the development of animal models of pancreatitis that 
more closely mimic human conditions.  

Premature activation of zymogens (inactive digestive enzymes) within 
the pancreatic acinar cell results in the release of active enzymes 
within pancreatic tissue, leading to autodigestion that may initiate 
pancreatitis. Cerulin, an analogue of CCK has been shown to cause 
zymogen activation in a time- and dose-dependent manner in pancreatic 
acinar cells, an effect which is enhanced by alcohol. Moreover, ethanol 
increased rat pancreatic amylase secretion and plasma CCK levels, which 
were mediated through CCK-releasing factor. Further research is 
required to understand the interactive effect of alcohol and CCK on 
zymogen activation.    

The pancreas can metabolize ethanol via oxidative as well as non-
oxidative pathways, generating acetaldehyde and fatty acid ethyl esters 
(FAEE), respectively. The major oxidative enzyme system employs alcohol 
dehydrogenase (ADH), and the non-oxidative pathway utilizes FAEE 
synthases. Acetaldehyde causes tissue injury through genotoxicity, 
adduct formation and associated immunotoxicity, but its role in causing 
pancreatitis needs clarification. In the oxidative pathway, in addition 
to ADH, alcohol may also be metabolized by cytochrome P4502E1 (CYP2E1), 
which has been shown to be induced in rat pancreas by chronic ethanol 
administration. Alcohol's metabolism by CYP2E1 results in the 
generation of reactive oxygen species (ROS), which may initiate tissue 
injury via activation of nuclear factor kappaB (NF-kB) and increased 
transcription of proinflammatory cytokines. Fatty acid ethyl esters 
have been shown to increase the fragility of pancreatic lysosomes which 
may release hydrolases capable of activating trypsinogen within the 
pancreas, thereby predisposing the pancreas to autodigestive injury. 
Additional studies are required to understand the relative role of 
oxidative and non-oxidative metabolism in ethanol-induced pancreatic 

One of the major features of chronic alcoholic pancreatitis is fibrosis 
resulting from increased production of extracellular matrix proteins, 
including collagen, by activated pancreatic stellate cells (PSCs). 
Although several factors such as acetaldehyde, oxidative stress, and 
cytokines have been implicated in mediating alcohol's effect on PSCs 
activation, the underlying molecular mechanisms need to be elucidated.   

In addition to direct effects of alcohol, various factors such as 
substance abuse, genetic makeup, bacterial and viral infection, 
smoking, high fat diet, compromised immune function, gallstones, and 
drinking patterns may render the pancreas more susceptible to alcohol-
induced tissue injury. Mechanisms underlying the interactive effects of 
alcohol and these predisposing factors need to be elucidated. 

Research Scope: 

Appropriate topics for investigation under this PA would include, but 
are not limited to:

o Elucidation of mechanisms by which alcohol induces or promotes    
premature activation of pancreatic enzymes (zymogens) within the 
pancreas directly or indirectly.      
o Characterization of the interactive effects of alcohol and  
cholecystokinin on the initiation and perpetuation of alcoholic 

o Determination of the role of diet, including fat and protein, in the     
modulation of gene expression and synthesis of various secretagogues. 

o Investigation of the role of acetaldehyde and fatty acid ethyl esters  
in the initiation and progression of alcoholic pancreatitis. 

o Determination of the role of oxidative stress in the activation of 
transcription factors that are involved in regulating proinflammatory 

o Determination of the roles of cytokines, chemokines, adhesion 
molecules, and inflammatory leukocytes in the initiation and 
progression of inflammation of the pancreas. 

o Investigation of the role of gut-derived endotoxin in triggering the 
process of inflammation through activation of pancreatic acinar cells 
and inflammatory leukocytes. 

o Characterization of the molecular mechanisms of pancreatic stellate 
cell activation leading to increased deposition of extracellular matrix 
proteins and fibrosis.   

o Investigation of the role of impaired immune function in rendering 
the pancreas more susceptible to the injurious effect of alcohol.  

o Determination of the influence of drinking patterns on the 
pathogenesis of the disease.   

o Investigation of the role of other factors such as substance abuse, 
smoking, bacterial and viral infection, gallstones, and genetic 
susceptibility in the initiation and progression of alcoholic 

o Determination of the influence of gender and ethnicity on the course 
of alcoholic pancreatitis. 

o Characterization of the relationship between pancreatitis, diabetes, 
obesity, and pancreatic cancer. 

o Identification and characterization of biomarkers of early cell or                      
tissue perturbation that can be used for diagnosis of the disease.  

o Study of pharmacology of drug-induced pancreatitis including that 
caused by non-nucleotide and protease inhibitor anti-retroviral 
therapeutic agents.   


This PA will use the NIH R01 and Exploratory/Developmental Research 
Grant (R21) award mechanisms 
( As 
an applicant, you will be solely responsible for planning, directing, 
and executing the proposed project.  Applications using the R21 
mechanism may request a project period of up to two years with a 
combined budget for direct costs of up $275,000 for the two year 
period.  For example, the applicant may request $100,000 in 
the first year and $175,000 in the second year.  The request should be 
tailored to the needs of the project.  Normally, no more than $200,000 
may be requested in any single year.  

This PA uses just-in-time concepts. It also uses the modular as well as 
the non-modular budgeting formats (see  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise 
follow the instructions for non-modular research grant applications.  
This program does not require cost sharing as defined in the current 
NIH Grants Policy Statement at

Exploratory/developmental grant support is for new projects only; 
competing continuation applications will not be accepted. Two revisions 
of a previously reviewed exploratory/developmental grant application may 
be submitted as defined in NIH Policy at


You may submit (an) application(s) if your institution has any of the 
following characteristics: 
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations


Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support.  Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.


We encourage inquiries concerning this PA and welcome the opportunity 
to answer questions from potential applicants. Inquiries may fall into 
two areas:  scientific/research and financial or grants management 

o Direct your questions about scientific/research issues to:

Vishnudutt Purohit, Ph.D.
Program Director
Biomedical Research Branch
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
6000 Executive Boulevard/ suite 402
Bethesda, M.D., 20892-7003
(for courier service use Rockville, MD 20852)
Phone: (301) 443-2689
Fax: (301) 594-0673

Jose Serrano M.D., Ph.D.  
Director Liver & Biliary  Programs  
Liver Disease Research Branch  
Division of  Digestive Diseases and Nutrition  
National Institute of  Diabetes and Digestive and Kidney Diseases  
2 Democracy Plaza, Room 657, MSC 5450  
Bethesda, M.D., 20892-5450 
(for courier service use 6707 Democracy Blvd, Room 657, Bethesda, M.D., 
Phone: (301) 594-8871  
Fax: (301) 480-8300  

Jag H. Khalsa, Ph.D.
Pharmacologist/Health Scientist Administrator
Center on AIDS & Other Medical 
  Consequences of Drug Abuse (CAMCODA)
National Institute on Drug Abuse, NIH
6001 Executive Blvd., Room 5098, MSC 9593
Bethesda, M.D., 20892-5953
(for courier service use Rockville, MD 20852)
Phone: (301) 443-1801, (301) 443-2159 (direct)
Fax: (301) 480-4544, or (301) 594-6566
o Direct your questions about financial or grants management matters 

Judy Fox (formerly Simons)
Chief, Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism 
6000 Executive Boulevard, Suite 504
Bethesda, MD 20892-7003
(for courier service use Rockville, MD 20852)
Telephone:  (301) 443-4704 
Fax:  (301) 443-3891 


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). Applications must 
have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements. The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. The PHS 398 is available 
at in an 
interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

The title and number of this PA must be typed on line 2 of the face 
page of the application.

APPLICATION RECEIPT DATES: Applications submitted in response to this 
program announcement will be accepted at the standard application 
deadlines, which are available at  Application deadlines are also 
indicated in the PHS 398 application kit.

requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail.  Applicants request direct costs in $25,000 
modules.  Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at includes step-
by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at

YEAR: Applications requesting $500,000 or more in direct costs for any 
year must contact the proper program official identified above to 
receive authorization to submit the proposal. The applicant must 
include a cover letter identifying the NIAAA program official who has 
agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following 
1)   Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff 
member and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended 
or revised version of these grant application types. Additional 
information on this policy is available in the NIH Guide for Grants and 
Contracts, October 19, 2001 at 

SENDING AN APPLICATION TO THE NIH: 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)

APPLICATION PROCESSING: Applications must be mailed on or before the 
receipt dates described at The CSR 
will not accept any application in response to this PA 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 a substantial revision of an 
application already reviewed, but such application must include an 
Introduction addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  Appropriate scientific review 
groups convened in accordance with the standard NIH peer review 
procedures ( will evaluate 
applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed 
to have the highest scientific merit, generally the top half of 
applications under review, will be discussed and assigned a priority 
o Receive a written critique
o Receive a second level review by the appropriate national advisory 
council or board.


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. The scientific review group will address and 
consider each of these criteria in assigning the application's overall 
score, weighting them as appropriate for each application.   

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
   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 analyses 
adequately developed, well-integrated, and 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 
methods? Are the aims original and innovative? Does the project 
challenge existing paradigms or develop new methodologies or 

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?  

human subjects and protections from research risk relating to their 
participation in the proposed research will be assessed. (See criteria 
included in the section on Federal Citations, below).
of plans to include subjects from genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals 
of the research will be assessed.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria 
in the sections on Federal Citations, below).

are to be used in the project, the five items described under Section f 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.  


Sharing Research Data 

Applicants requesting more than $500,000 in direct costs in any year of 
the proposed research are expected to include a data sharing plan in 
their application. The reasonableness of the data sharing plan or the 
rationale for not sharing research data will be assessed by the 
reviewers. However, reviewers will not factor the proposed data sharing 
plan into the determination of scientific merit or priority score.

BUDGET:  The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to 
be gained.

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required 
for all types of clinical trials, including physiologic, toxicity, and 
dose-finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of 
data and safety monitoring boards (DSMBs) is required for multi-site 
clinical trials involving interventions that entail potential risk to 
the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide 
for Grants and Contracts, June 12, 1998: 

SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible.   Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers 
will consider the data sharing plan but will not factor the plan into 
the determination of the scientific merit or the priority score. 

of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating 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 clinical research should read the "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(; a 
complete copy of the updated Guidelines are available at  
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

SUBJECTS: The NIH maintains a policy 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, 

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 is available at .

policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at and 
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see   It is the responsibility of the applicant to 
provide, in the project description and elsewhere in the application as 
appropriate, the official NIH identifier(s)for the hESC line(s)to be 
used in the proposed research.  Applications that do not provide this 
information will be returned without review.

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of 
"Healthy People 2010," a PHS-led national activity for setting priority 
areas. This PA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92. All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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Office of Extramural Research (OER) - Home Page Office of Extramural
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