FOODBORNE ILLNESSES, GASTROINTESTINAL AND RENAL COMPLICATIONS

Release Date:  November 30, 1999

RFA:  DK-00-005            

National Institute of Diabetes and Digestive and Kidney Diseases
American Digestive Health Foundation

Letter of Intent Receipt Date:  February 23, 2000 
Application Receipt Date:       March 23, 2000 

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT 
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS 
THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS 
RFA.

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases 
in partnership with the American Digestive Health Foundation invites 
experienced and new investigators to submit research grant 
applications to pursue basic and clinical investigations to further 
the understanding of foodborne illnesses and especially the 
gastrointestinal disease and renal injury of E. coli 015:H7-induced 
hemolytic uremic syndrome.  The proposed studies should foster and 
extend the understanding of the pathogenesis and pathophysiology of 
foodborne disease, including: the mechanisms by which bacterial 
toxins induce endothelial cell damage and renal injury; and the 
mechanisms by which bacterial, viral, and fungal organisms and 
products cause gastrointestinal and extra-gastrointestinal injury.  
Other areas which have potential for further investigation include 
genetic factors that determine gastrointestinal as well systemic 
diseases expression; markers of genetic susceptibility to 
complications of foodborne disease; the natural history and 
epidemiology of the enteric infection as well as the extra-
intestinal manifestations; the risk factors for the acquisition, 
transmission and expression of foodborne disease particularly in 
children and the elderly; human markers of genetic susceptibility to 
complications of foodborne disease; the development of experimental 
models of foodborne diseases; and the identification and testing of 
interventions that might lead to improved management of 
gastrointestinal disease as well as extra-gastrointestinal 
complications.  Of prime importance is the development of new 
diagnostic and therapeutic techniques that would lead to early 
medical intervention and prevention of complications of foodborne 
illnesses. 

The intent of this solicitation is to intensify investigator-
initiated research, to attract new investigators to the field, and 
to increase interdisciplinary research.  The ultimate aim is to 
encourage and facilitate research studies in this area where 
progress already attained offers new opportunities to increase the 
pace with which knowledge is accrued.

In recognition of the importance of these research questions, The 
American Digestive Health Foundation, a cooperative effort of the 
American Gastroenterological Association, the American Society of 
the Gastrointestinal Endoscopy, and the American Association for the 
Study of Liver Diseases, are co-sponsoring this solicitation and 
will be providing partial funding through NIH for direct costs of 
the portfolio of grants that receive support under this initiative.

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), FoodBorne Illness, Gastrointestinal 
and Renal Complications is related to one or more of the priority 
areas.  Potential applicants may obtain a copy of "Healthy People 
2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000 
 
ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit 
and non-profit organizations, public and private, such as 
universities, colleges, hospitals, and 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 RFA will use the National Institutes of Health (NIH) research 
project grant (R01) and the R21 mechanisms.   Responsibility for the 
planning, direction, and execution of the proposed project will be 
solely that of the applicant.  The R21 provides limited funds 
(maximum of $100,000 direct costs per year) for short-term (up to 
two years) research projects.  R21 grants are nonrenewable, but 
continuation of the projects developed under these grants can be 
supported by the investigator initiated research project grant (R01) 
mechanism. 

Specific application instructions have been modified to reflect 
“MODULAR GRANT”and “JUST-IN-TIME” streamlining efforts being 
examined by the NIH.  Complete and detailed instructions and 
information on Modular Grant applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

Modular Grant applications will request direct costs in $25,000 
modules.  The total direct costs must be requested in accordance 
with the program guidelines and the modifications made to the 
standard PHS 398 application instructions. 

FUNDS AVAILABLE

For FY 2000, $2.1 million dollars will be committed to fund 
applications submitted in response to this RFA.  It is anticipated 
that 10 to 12 awards will be made.  An applicant for an R01 award 
may request a project period of up to 5 years and a budget for 
direct costs of up to $200,000 (8 modules) per year, including 
Facilities and Administration (F & A) costs on consortium 
(subcontract) arrangements.  An applicant for an R21 award may 
request a project period of up to two years and a budget for direct 
costs of up to $100,000 (4 modules) per year, including F & A costs 
on consortium arrangements.  Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of the 
awards will also vary.  
Although the financial plans of the NIDDK, and the American 
Digestive Health Foundation (ADHF) provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of applications of 
outstanding scientific and technical merit.  At this time, it is not 
known if competing renewal applications will be accepted and/or if 
this RFA will be reissued.

RESEARCH OBJECTIVES

Background

While the United States food supply is among the safest in the 
world, every year there are millions of American stricken by 
foodborne illnesses.  The Centers for Disease Control and Prevention 
(CDC) estimate that there are up to 80 million foodborne-related 
illnesses per year.  Foodborne illnesses tend disproportionately to 
affect the very young and the elderly.  Threats to the food and 
water supply are numerous and varied, and include Escherichia coli 
(E. coli 0157:H7) in meat and juices, Salmonella in eggs or 
vegetables, Cyclospora on fruit, Cryptosporidium in drinking water, 
and hepatitis A virus in frozen berries.

In January 1997, a Presidential Initiative was announced requesting 
an increase in the 1998 federal budget to fund a nationwide early 
warning system for foodborne illnesses, increased seafood safety 
inspection, and expanded food safety research and training 
education.  The President directed the Departments of Agriculture 
and Health and Human Services (DHHS) and the Environment Protection 
Agency to identify specific steps to improve the safety of the food 
supply.  

This RFA is designed to support basic and clinical research on the 
biology, human genetics, and pathogenesis of the disease process, 
natural history and epidemiology of foodborne illnesses.  Because 
induction of foodborne illnesses is one mechanism through which 
bioterrorism may take place, an improved awareness of the 
pathobiology of foodborne illnesses and the underlying mechanisms 
should lead to more effective diagnostic approaches to these 
illnesses and provide better means of prevention and treatment.  
Relevant topics of research include, but are not limited to the 
following:

Objectives:

o Identification of mechanisms by which E. coli and other pathogen-
related toxins induce epithelial (cells of the gastrointestinal 
tract) and endothelial cell damage and mechanisms leading either to 
recovery or permanent damage within the kidneys and (or) the 
gastrointestinal tract.

o Development of experimental in-vivo models for studies of the 
pathogenesis of the disease and particularly to test therapies as 
these are identified; also the development of animal models of 
disease, such as genetically engineered mice that express modified 
levels of glycolipid receptors on endothelial cells. 

o Studies of human genetic susceptibility, i.e., host factors that 
regulate the survival of the pathogens in the gastrointestinal tract 
or the kidneys, and other host factors that determine the biological 
response to the initiating events, the severity of tissue injury, 
and the eventual disease outcome.  Included should be the role of 
the investigation of the remaining genes in the pathway of the 
verotoxin receptor.
 
o Studies of the sources, role, and mechanisms by which cytokines 
and other various inflammatory mediators elicit signals and/or 
traffic between the renal and gastrointestinal vascular endothelium 
with consequent long-term effects on kidney function and 
histopathology.

o Discerning the role of activated inflammatory cells in presenting 
endothelial injury, as well as the specific role of reactive 
nitrogen or oxygen molecules by activated monocytes and 
polymorphonuclear leukocytes.

o Studies of markers of gastrointestinal and renal injury, as well 
as markers of disease severity are encouraged.

o Enhancing the understanding of the role of the direct toxin damage 
to endothelial cells vs. toxin-induced cytokine damage.

o Studies of the mechanisms by which verotoxins cause 
changes/alterations in endothelial cell tight junctions with 
increased permeability and altered expression of cell surface 
adhesion molecules, leading to morphologic alterations and 
endothelial cell detachment characteristic of HUS; also, elucidation 
of the mechanisms leading to either endothelial cell recovery or 
permanent damage.

o Epidemiologic studies to characterize environmental as well as 
human genetic factors in familial clustering of foodborne illnesses 
and their extra-gastrointestinal manifestations.

o Development of intervention strategies to prevent the transit of 
the verotoxin, including the design and testing of soluble toxin 
receptor analogs in appropriate systems.

o Identification of host-based and clinical strategies to prevent 
complications of E.coli 0157:H7-related illnesses during the initial 
critical interval between the occurrence of hemorrhagic colitis and 
the development of HUS. 

Investigators are not limited to the above examples of the research 
focus and are encouraged to propose other approaches that are 
appropriate to the investigator initiated grant mechanism and to the 
requirements of this RFA.

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 was 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: http://grants.nih.gov/grants/guide/notice-files/not94-100.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 
March 23, 2000.

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://grants.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.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 23, 2000, 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 a subsequent application, the 
information that it contains allows IC staff to estimate the 
potential review workload and avoid conflict of interest in the 
review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities 
NIDDK, NIH
Building 45 Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600

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 301-435-0714, email: 
GrantsInfo@nih.gov.

The modular grant concept establishes specific modules in which 
direct costs may be requested as well as a maximum level for 
requested budgets. Only limited budgetary information is required 
under this approach.  The just-in-time concept allows applicants to 
submit certain information only when there is a possibility for an 
award. It is anticipated that these changes will reduce the 
administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application form PHS 398 (rev. 4/98) is 
to be used in applying for these grants, with the modifications 
noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 
modules, up to a total direct cost request of $200,000 per year for 
R01s or $100,000 for R21s. The total direct costs must be requested 
in accordance with the program guidelines and the modifications made 
to the standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $200,000 for R01s 
and $100,000 for R21s) and Total Costs [Modular Total Direct plus 
Facilities and Administrative  (F&A) costs] for the initial budget 
period Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete 
Form Page 4 of the PHS 398. It is not required and will not be 
accepted with the application.

o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 
the categorical budget table on Form Page 5 of the PHS 398. It is 
not required and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See 
http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs 
requested for each year.  This is not a Form page.

o Under Personnel, list key project personnel, including their 
names, percent of effort, and roles on the project.  No individual 
salary information should be provided.  However, the applicant 
should use the NIH appropriation language salary cap and the NIH 
policy for graduate student compensation in developing the budget 
request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each 
rounded to the nearest $1,000.  List the individuals/organizations 
with whom consortium or contractual arrangements have been made, the 
percent effort of key personnel, and the role on the project.  
Indicate whether the collaborating institution is foreign or 
domestic.  The total cost for a consortium/contractual arrangement 
is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any 
variation in the number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information 
used by reviewers in the assessment of each individual's 
qualifications for a specific role in the proposed project, as well 
as to evaluate the overall qualifications of the research team.  A 
biographical sketch is required for all key personnel, following the 
instructions below. No more than three pages may be used for each 
person.  A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, 
on research projects ongoing or completed during the last three 
years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, 
indicate the type of agreement and the date. All appropriate 
exclusions must be applied in the calculation of the F&A costs for 
the initial budget period and all future budget years.

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review. 

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 your 
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.

The sample RFA label is available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf 
format. 

Submit a signed, typewritten original of the application, including 
the Checklist, and three 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)

At time of submission, two additional copies of the application must 
be sent to:

Chief, Review Branch
Division of Extramural Activities, NIDDK
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600

Applications must be received by the application receipt date listed 
in the heading of this RFA.  If an application is received after 
that date, it will be returned to the applicant without review.  
Supplemental documents containing significant revision or additions 
will not be accepted, unless Applicants are notified by the 
Scientific Review Administrator.

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 
already reviewed, but such applications must include an introduction 
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the 
CSR and responsiveness by the NIDDK.  Incomplete and/or non-
responsive applications will be returned to the applicant without 
further consideration. 

If the application is not responsive to the RFA, NIDDK CSR staff may 
contact the applicant to determine whether to return the application 
to the applicant or submit it for review in competition with 
unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA 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 will be used by the initial review group in which 
applications 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 the applications under review, will 
be discussed, assigned a priority score, and receive a second level 
review by the NIDDK National Diabetes and Digestive and Kidney 
Diseases 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.

(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 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.

SCHEDULE

Letter of Intent Receipt Date: February 23, 2000
Application Receipt Date: March 23, 2000
Peer Review Date: June-July, 2000
NIDDK Advisory Council Review: September, 2000 
Anticipated Award Date: September 30, 2000 

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o scientific and technical merit (as determined by peer review
o programmatic priorities 
o program balance
o availability of funds

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Frank A. Hamilton, M.D., MPH
Chief, Digestive Diseases Program Branch
DDDN/NIDDK
Natcher, Bldg. Room 6AN12B
45 Center Drive MSC 6600
Bethesda, MD  20892 6600
Telephone: (301) 594-8877
FAX:       (301) 480-8300 
Email: hamiltonf@extra.niddk.nih.gov

Gladys Hirschman, M.D
Director, Chronic Renal Diseases
and Pediatric Nephrology Program, DKUHD
NIDDK
Natcher Bldg. Room 6AS-13
45 Center Drive, MSC 6600
Bethesda, Md. 20892-6600
Telephone (301) 594-7717
FAX:      (301) 480-3510
e-mail: gladys_hirschman@NIH.Gov     

Direct inquiries regarding fiscal matters to:

George Tucker, MBA
Deputy Chief, Grants Management Branch
Division of Extramural Activities
NIDDK/Natcher Bldg. 45/6AS49E
45 Center Drive
Bethesda, MD 20892
Telephone: 301 594-8853
FAX: 301 480-3504
Email: tuckerg@extra.niddk.nih.gov

Aretina Perry-Jones
Division of Extramural Activities
NIDDK, NIH
45 Center Drive
Room 6AN-38B 
Bethesda, MD  20892-6600
Telephone: (301)594-8862
FAX:  (301) 480-3504
Email: perrya@extra.niddk.nih.gov

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 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.


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.