Release Date: February 11, 1999

RFA:  AI-99-005


National Institute of Allergy and Infectious Diseases
National Center for Research Resources
National Eye Institute
National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences
Office of Research on Women's Health

Letter of Intent Receipt Date:  March 15, 1999
Application Receipt Date:  May 6, 1999



The National Institute of Allergy and Infectious Diseases (NIAID), the National
Center for Research Resources (NCRR), the National Eye Institute (NEI), the
National Heart, Lung and Blood Institute (NHLBI), the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of
Environmental Health Sciences (NIEHS), and the Office of Research on Women's
Health (ORWH) invite applications to develop new technologies to rapidly screen
normal and mutagenized mice in order to detect and characterize abnormal immune
responses, with an emphasis on immune dysfunction associated with autoimmune
disease.  This Request for Applications (RFA) addresses many of the
recommendations of the NIH Committee on "Priority Setting for Mouse Genomics and
Genetics Resources".  Applications for highly innovative exploratory/
developmental projects are being sought.


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 RFA, Immunological Phenotyping of
Mouse Mutants, is related to the priority area of diabetes and chronic disabling
conditions.  Potential applicants may obtain a copy of "Healthy People 2000"
(Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-
00473-1) through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).


Applications may be submitted by domestic for-profit and non-profit
organizations; public and private institutions, such as universities, colleges,
hospitals, laboratories, units of State and local governments; and eligible
agencies of the Federal government.  Foreign institutions are not eligible to
apply for this RFA.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.


The mechanism of support will be the exploratory/developmental (R21) research
grant.  This mechanism provides short-duration support for preliminary studies
of a highly speculative nature which are expected to yield, with this time frame,
sufficient information to form for basis for a rigorous series of further
investigations.  Applicants may request up to two years of support and up to
$150,000 per year in direct costs.  With compelling justification, exceptions to
these cost limitations can be made if specific costly reagents, animals,
specimens or laboratory modifications are needed to perform these studies. 
Program staff may be able to advise prospective applicants concerning relevant
resources available from NIAID-supported resources.  Contact Dr. Vicki Seyfert
at the address listed under INQUIRIES for further information on such NIAID-
supported resources.  Awards made under this RFA are not renewable; however,
applicants may elect to seek continuing support for this research through the
unsolicited research projects (R01) grant mechanism.

Specific application instructions have been modified to reflect the "MODULAR
GRANT APPLICATION AND AWARD" process which has been adopted by the NIH (see the
NIH Guide, December 15, 1998).

For this RFA, funds must be requested in $25,000 direct cost modules. A feature
of the modular grant is that no escalation is provided for future years, and all
anticipated expenses for all years of the project must be included within the
number of modules being requested.  Only limited budget information is required
and any budget adjustments made by the Initial Review Group will be in modules
of $25,000.

More detailed information about modular grant applications, including a sample
budget narrative justification pages and a sample biographical sketch, is
available via the Internet at url:


The estimated total funds (direct and indirect costs) available for the first
year of support for all awards made under this RFA will be $2,000,000.  In Fiscal
Year 1999, the participating Institutes and Centers (ICs) plan to fund 8 to 10
awards.  The usual PHS policies governing grants administration and management
will apply.  Although this program is provided for in the financial plans of the
participating ICs, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose and the receipt of a sufficient number of
applications of high scientific merit.  Funding beyond the first and subsequent
years of the grant will be contingent upon satisfactory progress during the
preceding years and availability of funds.



Transgenic and gene-targeted mutant mice represent extremely valuable tools for
biomedical research.  Scientists have recently developed strategies for
conducting large-scale mutagenesis in mice, providing even more powerful tools,
previously restricted to simpler experimental systems such as Drosophila and C.

The large scale application of random chemical mutagenesis and other more
targeted genetic techniques is expected to substantially tax the ability of
researchers to phenotype large numbers of mutant mice. In some instances, e.g.,
when mutations cause developmental abnormalities that are easily identified on
visual inspection, the problems involved in phenotypic screening are relatively
straightforward.  In contrast, mutations that affect immune cell populations
and/or immune function are most often not readily identifiable upon gross
examination.  Moreover, current assays for evaluating immune responses are
generally labor intensive and time consuming, often requiring the purification
of individual cell populations and the demonstration of antigen-specific or
lectin-stimulated immune responses over a period of days.  In many instances,
thorough characterization of immune function would require volumes of blood,
serum, or tissue that could be obtained only by sacrificing genetically unique

Many immune-mediated disorders, including autoimmune diseases, evolve over time
and may not be evident, even with a thorough microscopic and functional
evaluation performed at a single point in time.  Novel, high throughput
technologies are needed to assess immune development, immune function, loss of
immune self-tolerance, and autoimmune injury in mice. In other instances,
existing technologies might be adapted to provide higher throughput, rapid and
more accurate analysis, or scaled down using newer principles of micro and
nanofabrication.  In all cases, new technologies for phenotyping mouse mutants
should be rapid, accurate, relatively cost efficient and should minimize the
necessity to sacrifice valuable mutant mice.

Research Objectives and Scope

The objective of this RFA is to support the development of new technologies to
rapidly phenotype large numbers of mutant mice and assess the characteristics of
immune dysfunction in these animals with an emphasis on the susceptibility to,
and the initiation and progression of, autoimmune disease. Such technologies may
include, but are not limited, to the following:

o  High throughput assays for analyzing immune cell types and function from small
volumes of blood, including development of microfabricated devices for purifying
and characterizing cells and development of antigen or tethered antigen "chips"
for identification of antigen specific B or T cells;

o  Modification of existing technologies for characterizing antigen-specific T
cells using soluble MHC/tetramers, ELISPOT assays or laser-mediated cell
dissection from tissue samples;

o  High throughput assays for analyzing cytokine or chemokine levels in small
volumes of blood, serum, or tissue samples;

o  High throughput assays for assessing changes in gene expression in single
cells or small numbers of cells including development of microfabricated devices
to separate and isolate DNA, and to amplify and analyze DNA using cDNA

o  High throughput methods to extract individual cells from tissue samples;

o  High throughput assays to assess changes in protein expression from small
volumes of blood including development of antibody "chips" for evaluating
expression of specific proteins;

o  High throughput methods to extract individual cells from tissue samples;

o  Development of methods to accelerate autoimmune processes in susceptible
strains of mice, e.g., development of mouse strains which have genetic
backgrounds that enhance self-reactivity and autoimmunity, or development of
mouse strains that are more susceptible to immune deviation following exposure
to chemical or other environmental agents and;

o  Identification of markers for self-reactivity that can be adapted for use in
a high throughput assay.

Applicants are required to provide information on:  how proposed new technologies
or refinements to those in development represent improvements over current
methods; the aspects of immune function and autoimmunity to be tested; and the
levels of throughput that can be achieved (number of mice processed per
day/week).  Proposals to develop feasible early predictors of subsequent
autoimmune disease are especially encouraged since such screens would greatly
facilitate progress in the identification of informative mutants.


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, compelling rationale,
and justification are 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", published in the Federal Register of March 28, 1994 (FR 59 14508-
14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18,
1994 which is available via the WWW. at:


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 which is available at the following URL

Investigators may obtain copies from these sources or from the program contacts
at the address listed under INQUIRIES who may also provide additional relevant
information concerning the policy.


Prospective applicants are asked to submit, by March 15, 1999, a letter of intent
that includes a descriptive title of the overall proposed research; the name,
address and telephone number of the Principal Investigator; and the number and
title of this RFA.  Although the letter of intent is not required, is not
binding, does not commit the sender to submit an application, and does not enter
into the review of subsequent applications, the information that it contains
allows NIAID staff to estimate the potential review workload and to avoid
conflict of interest in the review.  The letter of intent is to be sent to Dr.
Madelon Halula at the address listed under INQUIRIES.


Applicants are strongly encouraged to call the program contacts listed in
INQUIRIES below with any questions regarding the responsiveness of their proposed
project to the goals of this RFA.

The research grant application form PHS 398 (rev. 4/98) is to be used in applying
for these grants.  Application kits are available at most institutional offices
of sponsored research and 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: Applications are also available on the World Wide Web


o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments) 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.

of the PHS 398.  It is not required and will not be accepted with 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 - Use a Modular Grant Budget Narrative page.
(See for sample pages.) 
At the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should be

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.  The total cost for a consortium/contractual arrangement is
included in the overall requested modular direct cost amount.

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:

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

o  OTHER SUPPORT - Form Page 7.  This form must be completed for applications in
response to this RFA to allow awards to be negotiated and made on or before
September 30, 1999.

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. It is important to identify all exclusions that were used in the
calculation of the F&A costs for the initial budget period and all future budget

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.

Applications not conforming to these guidelines will be considered unresponsive
to this RFA and will be returned without further review.

The RFA label available in the application form PHS 398 must be affixed to the
bottom of the face page.  Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee in
time for review.  In addition, the RFA title and number must be typed on line 2
of the face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
checklist, and three signed, exact, single-sided photocopies, in one package to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional exact copies of the application and all
five sets of any appendix material must be sent to Dr. Madelon Halula at the
address listed under INQUIRIES.  These copies must be sent at the same time as
the original and three copies are sent to the Center for Scientific Review (CSR),
failure to do so will prevent the application from being peer reviewed in time
for award in fiscal year 1999.

Applications must be received by May 6, 1999.  If an application is received
after that date, it will be returned to the applicant without review.  The 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.


Upon receipt, applications will be reviewed for completeness and adherence to the
Special Instructions above by CSR and for responsiveness by NIAID staff. 
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 NIAID 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
National Advisory Allergy and Infectious 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.  The
reviewers will comment on the following aspects of the application in their
written critiques 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 by the reviewers 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 a 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

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?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific goals of the
research and plans for the recruitment and retention of subjects; the provisions
for the protection of human and animal subjects; and the safety of the research


Letter of Intent Receipt Date:  March 15, 1999
Application Receipt Date:       May 6, 1999
Scientific Review Date:         July 1999
Advisory Council Date:          September 1999
Earliest Award Date:            September 30, 1999


Funding decisions will be made on the basis of scientific and technical merit as
determined by peer review, program balance, and the availability of funds.  The
earliest anticipated date of award is September 30, 1999.


Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is

Direct inquiries regarding programmatic issues to:

Dr. Vicki Seyfert
Division of Allergy Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4A21
Bethesda, MD  20892-7610
Telephone:  (301) 496-7551
FAX:  (301) 402-2571

John D. Strandberg, D.V.M., Ph.D.
Comparative Medicine
National Center for Research Resources
6705 Rockledge Drive, MSC 7965
Bethesda, MD  20892-7965
Telephone:  (301) 435-0744 or 435-0884
FAX:  (301) 480-3819

Dr. Ellen S. Liberman
Lens and Cataract and Glaucoma Programs
National Eye Institute
6120 Executive Boulevard, Suite 350, MSC 7164
Bethesda MD  20892-7164
Telephone:  (301) 496-0484
FAX:  (301) 402-0528

Barbara Linder, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN18A
Bethesda, MD  20892
Telephone: (301) 594-0021
FAX: (301) 480-3503

John Fakunding, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9200, MSC 7940
Bethesda, MD  20892
Telephone:  (301) 435-0544
FAX: (301) 480-1454

Jerrold J. Heindel, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone: (919) 541-0781
FAX:  (919) 541-5460

Direct inquiries regarding review issues and special instructions for application
preparation; address the letter of intent to; and mail two copies of the
application and all five sets of appendices to:

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 402-2636
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Pamela G. Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4C25
Bethesda, MD 20892-7610
Rockville, MD 20852 (for express/courier service
Telephone:  (301) 402-6580
FAX:  (301) 480-3780


This program is described in the Catalog of Federal Domestic Assistance Nos.
93.856 and 93.855.  Awards are made under authorization of the Public Health
Service Act, Sec. 301 (c), Public Law 78-410, as amended.  Awards will be
administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and
45 CFR Part 74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems review.

The Public Health Service strongly encourages all grant and contract 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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