INNOVATIVE AND EXPLORATORY RESEARCH IN DIGESTIVE DISEASES AND NUTRITION

RELEASE DATE:  June 8, 2004

PA NUMBER:  PA-04-108

EXPIRATION DATE:  After June 1 2007, unless reissued. 

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:  
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION: 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)
National Cancer Institute (NCI)
 (http://www.nci.nih.gov)
Office of Dietary Supplements (ODS)
 (http://dietary-supplements.info.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.848, 93.393

THIS PA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE OF THIS PA 
 
The Division of Digestive Diseases and Nutrition at the National Institute of 
Diabetes and Digestive and Kidney Diseases (NIDDK) and the Division of Cancer 
Prevention at the National Cancer Institute (NCI) invites applications 
through the exploratory/developmental (R21) grant mechanism from 
investigators with research interests in gastroenterology, hepatology, 
obesity, and nutrition and that serve the mission of NIDDK and NCI. The aim 
of this program announcement is to stimulate the application of highly novel 
approaches to important areas of digestive diseases (including associated 
cancers) and nutrition research.  This mechanism is primarily aimed at 
attracting and supporting new investigators in these research fields. Patient 
oriented or epidemiological research will not be supported through this 
Program Announcement and should be submitted according to 
http://grants.nih.gov/grants/guide/pa-files/PAR-04-082.html.

Applications will be accepted only from (1) newly independent investigators 
or (2) established investigators developing a completely new line of 
research. Results obtained from the R21 grant should allow subsequent 
submission of R01 applications focusing on research problems relevant to the 
study of digestive diseases and nutrition. These grants are not intended to 
support or supplement ongoing funded research of an established investigator, 
or to serve as an alternative mechanism of support for projects not receiving 
funding as competitive continuation applications.

The R21 is intended to encourage exploratory and developmental research 
projects by providing support for the early and conceptual stages of these 
projects. The characteristics, requirements, preparation, and review criteria 
for the R21 application are described. For additional information 
investigators are strongly encouraged to consult the R21 website at 
http://grants.nih.gov/grants/funding/r21.htm. 

RESEARCH OBJECTIVES

By using the R21 mechanism, the NIDDK and NCI seek to foster the introduction 
of novel scientific ideas, model systems, tools, agents, targets, and 
technologies that have the potential to substantially advance biomedical 
research.  

Areas of special interest in this PA include but are not limited to:

o  Identification of novel signaling molecules and pathways involved in 
cellular and tissue development, differentiation, gene transcription, and 
function of the gastrointestinal tract, exocrine pancreas, liver and 
adipocytes, including their interactions with bioactive food components.

o  Identification and characterization, isolation of gastrointestinal, 
pancreatic and hepatic stem cells. Identification and characterization the 
differentiation factors and processes determining gastrointestinal, 
pancreatic and adipose stem cells development into mature tissues and its 
potential uses as therapeutic alternatives.

o  Characterization of gastrointestinal neuroendocrine cell and enteric 
nervous system and their role in gastrointestinal  motility and nutrient 
absorption and bioavailability. Nutrient-gene interaction and regulation of 
gene expression .

o  Genomics, proteomics and metabolomics as related to nutrition and its 
impact on digestive diseases.

o  Gastrointestinal, hepatic, and pancreatic cell regeneration and adaptive 
responses to aging and injury mechanisms. The role of telomers and telomerase 
activity in tissue regeneration, dysplasia and aging in the setting of 
chronic injury and carcinogenesis.

o  Development, characterization and utilization of novel cellular and animal 
models of gastrointestinal, pancreatic and hepatic diseases, including 
associated cancers.
 
o  Development of biological markers for staging and prognosis in diseases 
such us celiac disease, pancreatitis, pancreatic cancer,  inflammatory bowel 
disease, functional GI disorders, colorectal cancer, immune and viral 
hepatitis, hepatic cancer, obesity and nonalcoholic steatohepatitis (NASH).

o  Development of novel vectors and delivery systems for use in gene therapy 
of gastrointestinal, pancreatic, hepatobiliary and nutritional diseases.

o  Validation of exfoliated cells as indicators of the utilization of 
bioactive food components and their abilities to alter nutritional epigenomic 
and transcriptomic events.

o   Basic research leading to innovative preventive and therapeutic 
interventions as they may relate to bioactive food components and/or dietary 
supplements.

o  Development of new methods for temporal and spatial control of transgene 
expression in gastrointestinal, pancreatic, hepatic and adipose 
tissues/cells. High output characterization of gene expression and function 
from parenchymal and epithelial cells under physiological and pathological 
conditions, using microarrays, proteomics, RNA interference, differential 
display reverse transcriptase-polymerase chain reaction.

o  Identification of genes involved in susceptibility, phenotypic variation 
or response to therapy of gastrointestinal, hepatobiliary and pancreatic 
diseases or animal models of these diseases.  

o  Development of animal and in vitro cellular models and test systems to 
investigate the mechanisms of drug-induced liver disease and explore 
innovative preventive and therapeutic interventions (replenishment of GSH or 
chaperon molecules) during acute episodes, or as preventive measures in 
situation of high hepatotoxic potential (chemotherapies)or prior to liver 
collection of transplant.

o  Development of novel non invasive imaging methods to study function of the 
gastrointestinal tract, liver, pancreas and adipose tissue and pathogenic 
processes such as fibrosis, inflammation, hyperplasia, fat body accumulation.

o  Development of nanotechnologies to study function of the gastrointestinal 
tract, liver, pancreas and adipose tissue as related to diet.

o  Elucidation of the pathogenesis of digestive and nutritional diseases of 
unknown or poorly defined cause, such as celiac disease, ulcerative colitis, 
Crohn’s disease, childhood motility disorders, functional bowel disease, 
chronic idiopathic pancreatitis, pancreatic cancer, primary biliary 
cirrhosis, sclerosing cholangitis, congenital hepatic fibrosis autoimmune 
hepatitis, biliary atresia and childhood cholestatic liver diseases.

MECHANISM(S) OF SUPPORT 

Applicants responding to this PA must use the NIH Exploratory/Developmental 
Research Grant (R21) award mechanism.  The applicant will be solely 
responsible for planning, directing, and executing the proposed project. 

The applicant 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 budgeting 
format (see http://grants.nih.gov/grants/funding/modular/modular.htm).   All 
applications submitted in response to this announcement must use the modular 
budget format.  This program does not require cost sharing as defined in the 
current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm.  

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 
http://grants.nih.gov/grants/policy/amendedapps.htm.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: (ICs should select all categories that apply).

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
o Faith-based or community-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

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.  

WHERE TO SEND INQUIRIES

We encourage your 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 issues:

o Direct your questions about scientific/research issues to:

José Serrano M.D., Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 627
Bethesda, MD 20892-5458
Telephone: (301) 594-8871
Fax:  (301) 480-8300
Email: js362q@nih.gov

Sharon Ross Ph.D. 
Nutritional Science Research Group, 
Division of Cancer Prevention,
National Cancer Institute
6130 Executive Blvd. Suite 3157 
Bethesda, MD 20892-7328
Telephone: 301-594-7547 
Fax: 301-480-3925
Email: sr75k@nih.gov

o Direct your questions about financial or grants management matters to:

Donna Huggins
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 711
Bethesda, MD  20892-5458
Telephone:  (301) 594-8848 
FAX:  (301) 480-3504 
Email:  dh48v@nih.gov

SUBMITTING AN APPLICATION

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 http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of  
the face page of the application form and the YES box must be checked.

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

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 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  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 unfunded version 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.

PEER REVIEW PROCESS

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 
(http://www.csr.nih.gov/refrev.htm) 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 score.
o Receive a written critique.
o 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 evaluate 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 the following 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 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?  

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of 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). 
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm.

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both 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).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals 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.  

AWARD CRITERIA

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

REQUIRED FEDERAL CITATIONS 

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

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. 
http://ohrp.osophs.dhhs.gov/humansubjects/guidance/45cfr46.htm.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy 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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
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 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 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. 

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 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
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. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and 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 site.

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 http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ 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)(cite appropriate authorizations) 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 
http://grants.nih.gov/grants/policy/policy.htm.

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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Department of Health and Human Services

National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892