ORAL MICROBIOLOGY/IMMUNOLOGY OF TYPE 1 DIABETES

Release Date:  January 30, 2001

RFA:  RFA-DE-01-001

National Institute of Dental and Craniofacial Research
 (http://www.nidcr.nih.gov)

Letter of Intent Receipt Date:  March 12, 2001
Application Receipt Date:       April 12, 2001


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

PURPOSE

The purpose of this RFA is to encourage submission of applications for two 
year exploratory grants (R21) that will broaden research on the oral 
microbiology and immunology of Type 1 diabetes.  In particular, research is 
needed on the oral microflora, cytokines and antibodies in the subgingival 
crevice.  Applications that propose an integrated effort from investigators 
with expertise in a variety of scientific disciplines, or are from women, 
underrepresented minority or disabled scientists are particularly encouraged.  

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 Request for Applications (RFA), 
ORAL MICROBIOLOGY/IMMUNOLOGY OF TYPE 1 DIABETES, is related to the priority 
area, Oral Health.  Potential applicants may obtain a copy of "Healthy People 
2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

Research projects will be supported with the exploratory/developmental 
research grant (R21).  The Exploratory/Developmental research mechanism (R21) 
is used for support of creative, novel, and/or high risk/high payoff 
approaches that could produce innovative advances in this field.  This 
includes feasibility studies, protocol planning, and the incorporation of new 
disciplines and technologies. This mechanism provides the means to acquire the 
necessary pilot information, to attract talented new investigators from 
related disciplines, and to foster the development of interdisciplinary, 
inter-institutional collaborative efforts among investigators with diverse 
training and expertise.  

Applicants may request $100,000 in direct costs per year for up to two (2) 
years of support.  The anticipated award date is August 2001.

These awards are not renewable.  If desired, the specific aims of the R21 
project may be incorporated into a traditional research project grant 
application (R01) submitted prior to the termination of the R21 award. 

This RFA is a one-time solicitation.  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant. Future unsolicited competing continuation applications will compete 
with all investigator-initiated applications and be reviewed according to the 
customary peer review procedures.  

FUNDS AVAILABLE 

The NIDCR intends to commit approximately $500,000 in FY 2001 to fund 3 to 4 
grants in response to this RFA.  An applicant may request a project period of 
up to two (2) years and a budget of up to $100,000 direct costs per year.  
Because the nature and scope of the research proposed may vary, it is 
anticipated that the size of each award will also vary.  Although the 
financial plans of the NIDCR 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 meritorious applications. 

RESEARCH OBJECTIVES

Background

Nearly 16 million people in the United States have diabetes, a leading 
contributing factor for severe and extensive periodontal (gum) diseases.  
Recent studies indicate that diabetes alters the immune system and connective 
tissue, making the patient more susceptible to oral tissue destruction and 
inflammation.  Bacterial pathogens in the gingival crevice appear to utilize 
the weakened host to colonize, grow and induce periodontal disease.  

Type 2 diabetes accounts for about 90 percent of diabetes cases in the United 
States.  Type 2 is most common in people who are overweight, inactive, age 40 
and older, and have a family history of diabetes.  About 10 percent, or 1.6 
million of people with diabetes, have type 1, formerly known as juvenile onset 
diabetes or insulin-dependent diabetes.  This form of diabetes, which usually 
occurs in children and adults under age 30, develops when the body's immune 
system attacks the insulin-producing cells of the pancreas.

Periodontal infections occur more frequently in both Type 1 and Type 2 forms 
of diabetes.  The Workshop on Oral Diseases and Diabetes, held December 1999, 
concluded that, in order to advance the diagnosis, prevention and treatment of 
periodontal diseases in these patients, more data are needed on the oral 
microbiology and immunology of diabetes and recommended that the NIDCR support 
research on these topics.  A summary of this workshop is available on the 
NIDCR website: 
http://www.nidcr.nih.gov/news/strat-plan/Oral_Diseases&Diabetes.pdf.  

The current initiative is intended to encourage grant proposals to explore the 
microbiology and immunology of Type 1 diabetes. These R21 grants are expected 
to help grantees obtain preliminary data for new or competing R01 
applications.  Applications that address health disparities are particularly 
encouraged.  Applications that capitalize on the strengths of collaboration 
between clinicians and scientists to maximize the potential for discovering 
novel approaches relevant to oral infections of Type 1 diabetes are strongly 
encouraged.

Other

The present initiative seeks applications that focus specifically on the oral 
microbiology and immunology of Type 1 diabetes.  Applications from broadly 
interdisciplinary teams are appropriate and encouraged.  Research on Type 2 
diabetes will be considered only if the results would directly apply to Type 1 
diabetes. 
  
Examples of research topics that would be responsive to this RFA include, but 
are not limited to:

o Novel animal models (genetically characterized mice, SCID mice, gene 
knockout mice) to dissect the mechanisms of pathogenesis and to study oral 
infectious diseases associated with diabetes;

o Natural history of oral infections in diabetes from a microbial perspective;

o Large scale, state-of-the-science DNA probe analyses to identify and compare 
the microflora in patients with diabetes to that found in healthy controls;

o Microbe-host cell molecular interactions;

o Etiology and pathogenesis of pulpal and periapical infections in patients 
with diabetes;

o Effect of diabetes treatments on the oral microflora;

o Immune response within the oral cavity of the diabetes patient, including, 
for example, synthesis, structure and secretion of sIgA; number and type of 
lymphocytes; innate immune responses; and cytokines, lymphokines, and 
antibodies; and, 

These examples are meant to be illustrative of the general types of research 
approaches that would be considered appropriate for this RFA, and are not 
restrictive.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are 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 research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at  
https://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff 
member listed under INQUIRIES.  Program staff may also provide additional 
relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit 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 this 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 NIDCR staff 
to estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. H. George Hausch (see address below) 
by March 12, 2001.

APPLICATION PROCEDURES

Applicants are strongly encouraged to contact NIDCR staff members with any 
questions regarding the responsiveness of their proposed project to the goals 
of this RFA or the preparation of their applications.  

Applications are to be submitted on the grant application for PHS 398 (rev. 
4/98).  These forms are available at most institutional offices of sponsored 
research; from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910, telephone 301/710-0267,email: grantsinfo@nih.gov; and on the 
internet at https://grants.nih.gov/grants/funding/phs398/phs398.html

The instructions accompanying PHS 398 must be followed as far as possible but 
some modifications are necessary. The Research Plan (Specific Aims, Background 
and Significance, Preliminary Studies, and Research Design and Methods) may 
not exceed ten (10) pages.  No appendix material may be submitted. Graphs, 
diagrams, tables, charts and photographs must be included in the body of the 
application. Original glossy photographs should be included in the original 
application sent to the Division of Research Grants, NIH, and in the two 
copies sent to the Scientific Review Branch, National Institute of Dental and 
Craniofacial Research.  Applicants are reminded that the type size limitations 
specified in the General Instructions of PHS 398 must be observed. 
Applications not conforming with these instructions will be returned to the 
applicant without review. 

MODULAR APPLICATION DETAILS:

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts.  Complete and detailed 
instructions and information on Modular Grants can be found at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

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 maximum of $100,000 direct costs per year for two (2) years.  
The 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: For item 2, check YES, and insert Number DE-01-001, Oral 
Microbiology/Immunology of Type 1 Diabetes. For item 6, the maximum project 
period is two (2) years, and for item 7a, the maximum request is $100,000 
direct costs. 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 https://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 all 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, F&A) 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 all 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 
personnel, following the instructions below. No more than three pages may be 
used for each person. A sample biographical sketch may be viewed at: 
https://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 PAGE LIMITATION - In keeping with the pilot/feasibility nature of the 
requested studies the Research Plan (specific aims, background and 
significance, preliminary data and research design and methods) is limited to 
10 pages.  Tables and figures must be included in the 10-page limitation.

o APPENDIX - An appendix or additional supporting materials will not be 
accepted with the exception of originals of photos used in the application.  

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.  Type the RFA 
number on the label.  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.  

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

If the application submitted in response to this RFA is substantially similar 
to a grant application already submitted to the NIH for review, but that has 
not yet been reviewed, the applicant will be asked to withdraw either the 
pending application or the new one.  Simultaneous submission of identical 
applications will not be allowed, nor will essentially identical applications 
be reviewed by different review committees.  Therefore, an application that is 
essentially identical to one that has already been reviewed cannot be 
submitted in response to this RFA.  This does not preclude the submission of 
substantial revisions of applications already reviewed, but such applications 
must include an introduction addressing the previous critique.

Submit a signed, typewritten original of the application, including the 
Checklist, and three (3) 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 the time of submission, two (2) additional copies of the application must 
be sent to Dr. H. George Hausch in the NIDCR 
Scientific Review Branch at the address listed below. 

Applications must be received by April 12, 2001.  If an application is 
received after that date, it will be returned to the applicant without review.
  
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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

REVIEW CONSIDERATIONS

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

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 NIDCR in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the NIDCR Advisory 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 both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

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

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

(Additional scientific/technical merit criteria specific to the objectives of 
the RFA and the mechanism used must be included if they are to be used in the 
review.)

Schedule

Letter of Intent Receipt Date:    March 12, 2001
Application Receipt Date:         April 12, 2001
Peer Review Date:                 June 2001
Council Review:                   August 2001
Earliest Anticipated Start Date:  August 2001

AWARD CRITERIA

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

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Dennis Mangan, Ph.D.
Infectious Diseases and Immunity Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-32F
Bethesda, MD 20892-6402
Telephone: (301) 594-2421
FAX: (301) 480-8318
Email: Dennis.Mangan@nih.gov

Direct inquiries regarding review issues to:

H. George Hausch, Ph.D.
Scientific Review Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44F
Bethesda, MD  20892-6402
Telephone: (301) 594-2904
FAX: (301) 480-8303
Email: George.Hausch@nih.gov

Direct inquiries regarding fiscal matters to:

William Powell
Grants Management Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-44K
Bethesda, MD 20892-6402
Telephone: (301) 594-4800
FAX: (301) 480-8301
Email: William.Powell@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.121, Oral Diseases and Disorders Research Awards.  Awards are made under 
authorization of Sections 301 and 405 of the Public Health Service Act as 
amended (42 USC 241 and 284) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  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.

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