NIDDK BIOTECHNOLOGY CENTERS

Release Date:  September 23, 1999

RFA: DK-00-002

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date: January 14, 2000
Application Receipt Date: February 16, 2000 

PURPOSE

The purpose of this RFA is to make comprehensive gene expression technologies
widely available to researchers working in areas supported by NIDDK.  This RFA
seeks to establish Biotechnology Centers that will provide genomic profiling
resources to investigators working in research areas within the NIDDK's
mission.  A companion RFA (DK-00-003) for small grants to supplement existing
NIDDK grants to make gene profiling technology accessible on a 
project-by-project basis will also be issued. 

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. 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 for-profit and nonprofit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of
the Federal government.  Foreign institutions are not eligible for this
solicitation.  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) resource-related
(R24) grant mechanism award. Awards will be administered as stated in the NIH
Grants Policy Statement.

This RFA is a one-time solicitation.  The total requested project period for
an application submitted in response to this RFA may not exceed 3 years. The
maximum dollar request is limited to $350,000 of direct costs for each 
budget year. All major equipment should be included in the first budget year. 
It is anticipated that the budget for years 2 and 3 will provide for pilot and
feasibility studies of future projects using this technology.  Future 
unsolicited competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the customary
peer review procedures.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.  The
anticipated award date is September 30, 2000.

FUNDS AVAILABLE

For FY 2000, $4 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that about 8 Biotechnology Centers
will be funded.  However, this funding level is dependent upon the receipt of
a sufficient number of applications of high scientific merit.  Although this
program is provided for in the financial plans of the NIDDK, the award of 
grants pursuant to this RFA is also contingent upon the availability of funds
for this purpose.

RESEARCH OBJECTIVES

A. Background

The tremendous acceleration in pace of scientific discovery over the last
decade, coupled with development of many new high-throughput technologies, has
created an era of unparalleled opportunity to uncover the causes of disease
and identify effective therapies.  In particular, the Human Genome Project and
related efforts to identify at least some unique pieces of all expressed genes
(expressed sequence tags, ESTs) in the human genome has resulted in an
explosion of data and potential tools that will aid research in virtually all
fields of medicine.  The recent development of genome-wide expression
profiling (chip, microarray or Serial Analysis of Gene Expression [SAGE]
technologies) allows a comprehensive high-throughput screening of the effects
of an insult (genetic, physiologic, pathologic, etc.) on gene expression in
tissues and specific cell populations of interest.  These techniques may aid
in determining the function of a newly discovered gene or discovering new 
biomarkers and therapeutics for patients with disease.  Many investigators
with hypothesis-driven research programs want access to emerging technologies. 
Cost is a major obstacle to the application of these techniques by large
numbers of investigators.  The investment required to obtain essential
equipment and personnel to establish this technology is more than can easily
be borne by a single investigator.

B. Objectives and Scope

This RFA is intended to support the cost-effective introduction of techniques
to measure patterns of gene expression in specific tissues of interest to the
NIDDK-supported investigators.  This RFA will allow the formation of support
facilities that may include, but are not limited to:

1. cDNA Microarrays.  The applicant might propose to print, read, and analyze
microarrays.  The arrays might contain mixtures of cDNAs obtained from
commercial vendors, the Cancer Genome Anatomy Project (CGAP), or ESTs obtained
locally and of specific interest to the investigators.  It is anticipated that
each printing unit will distribute arrays to 7 to 20 NIDDK investigators. 
Applicants are expected to identify the sources of the cDNAs, reference all
genes to a genomic database (Entrez, Unigene, Locus Link, etc.), and indicate
plans to distribute arrays to the NIDDK community at a reasonable cost. 
Applicants need not include budgets for equipment for printing or reading
arrays or for bioinformatics support if they can obtain the necessary reagents
or support from collaborative efforts or commercial sources.

2. Oligonucleotide chips. The applicant might propose to produce, hybridize,
read, and/or analyze gene chips from commercial or academic sources. 
Applicants are expected to discuss the source and composition of the chips,
and details of the bioinformatic support. 

3. Serial Analysis of Gene Expression (SAGE). The applicant might propose to
construct high quality cDNA libraries, link and sequence the SAGE tags, and
analyze SAGE tags.  Applicants are expected to discuss library quality,
sequence fidelity, bioinformatic processing of SAGE tags, and statistical
issues.

Creation and maintenance of these technologies may require the collaboration
of investigators with expertise in many fields, such as molecular biology,
robotics, bioinformatics, genomics, and statistics.  In addition, key aspects
of infrastructure may also be supported and might include the development and
maintenance of appropriate databases and specialized equipment.  It is 
important to emphasize that there are a variety of approaches to genome-wide
expression analysis.  Therefore, a given strategy must be rigorously justified 
and must demonstrate that all key personnel are involved in the formulation of
the rationale and approach.

An objective of this RFA is to provide biotechnology support for both on-going
and new hypothesis-driven research projects. Therefore, applicants will be
required to describe projects that will benefit from these technologies.

C. Annual Meetings

The Principal Investigator must be willing to be part of a Steering Committee
consisting of representatives of each Biotechnology Center.  Annual meetings
will be held to encourage exchange of information among investigators who
participate in this program.  A major goal of these meetings is to facilitate
progress by providing a forum that will lead to sharing skills, ideas,
technology, data, and biological reagents.  At the meetings, participants will
also discuss quality assurance, bioinformatics, coordination, and training.
      
D. Sharing Data and Biological Materials in Human Genetic Research

Timely sharing of information, materials, and technology will speed scientific
discovery by permitting researchers access to sufficiently large and
well-characterized resources as quickly as possible.  This sharing of 
materials and data, including those that have not yet or may never be
published, is essential to rapid progress and will help to avoid unnecessary
duplication of large data collections. 

It is recognized that time may be required to verify the accuracy of data, to
perform initial analyses, and to protect intellectual property rights to
ensure that inventions, including therapeutic agents, are pursued and 
developed rapidly for the benefit of the public.  Thus, a protected period,
from the time data and materials are collected to the time they are made
available to other qualified investigators, may be appropriate.  The onset 
and duration of the period will vary, depending upon the nature of the
research project.  Applicants must justify the length of the protected period.

Where appropriate, grantees may work with the private sector to make unique
resources available to the larger biomedical research community at a
reasonable cost. Applicants may request funds to defray the costs of 
sharing materials or submitting data, with adequate justification. 

Post-Award Management
 
During the course of the grant period, technologies will improve, genomic
technologies will evolve, and the rate of progress and focus of work supported
by the grant(s) may change.  It is expected that the Principal
Investigator(s), after consultation with NIDDK program staff, will make any
necessary adjustment in scientific direction to accommodate the changing
environment.  In order to ensure that the project(s) remains focused on 
appropriate goals, maintains excellent coordination with the other projects
funded under this RFA, incorporates new technological advances and makes
sufficient progress, scientific and programmatic visits to the grantees will 
be conducted at a frequency to be negotiated with the awardees.

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 new 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 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: 
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators may also 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 January 14, 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 NIDDK 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
Natcher Building, Room 6AS-37F
45 Center Drive MSC 6600
Bethesda, MD 20892-6600 
Telephone: (301) 594-8885
FAX: (301) 480-3505

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 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 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 February 16, 2000.  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 previously reviewed, but such
applications must include an introduction addressing the previous critique.

Special Instructions to Applicants

The applicants must carefully justify methodologies, technologies,
bioinformatics, statistical analytical tools, and costs, and describe the
limitations of the approaches. Genome-wide expression analysis is a rapidly 
evolving field. Hence, applicants must discuss how they will be poised to take
advantage of technical and methodological advances and their impact on the 
throughput and costs proposed.

Scientific Application to Hypothesis-Driven Research Projects: Applicants must
include descriptions of 5 to 10 ongoing representative projects that will use
the gene profiling technology.  Applicants must also include descriptions of
several pilot and feasibility studies for new projects that will use this
technology.  These projects should be proposed for budget years 2 and 3.  
The project descriptions should be short (0.5-1 pages each) and included in
the Experimental Design and Methods portion of the application.  The
application must indicate how the projects will benefit from the new 
technology and how the results will be used in subsequent experiments.

Training and Education: Currently, only a few NIDDK-supported investigators
are in a position to use genomic technologies.  To address this deficiency,
each application must include plans to establish training and education
programs.  These programs should train local investigators to use these
techniques.  In addition, the applicants should indicate their willingness to
provide service and training to the larger NIDDK community.  The methods and
procedures for selecting qualified individuals and the duration and types of
service or training should be delineated in the application.

Internal Advisory Committee: The application must describe the composition and
functions of an internal advisory committee that would meet to discuss, for 
example, quality control, prioritization of resources, funding of pilot
projects in years 2 and 3, training, sharing of reagents and experimental
data, and adaptation to changing technologies. 

Annual Meetings: Applicants must include travel funds that will allow the
Principal Investigator and at least one other key research scientist to
participate each year for a one-day meeting in Bethesda, Maryland.  
Applications should include a statement indicating willingness to participate
in these meetings.

Sharing of Data and Biological Materials: In order to ensure the timely
sharing of information and materials, applicants will be requested to describe
in detail how, when, and in what manner data, materials, and technology 
will be made available to the scientific community.  In addition, the
applicant should outline how the rights and interests of the participants in
genetic research will be assured.

Applicants should discuss any pre-existing intellectual property rights,
including options to for-profit research sponsors, who might be associated
with the clones, sequences, and experimental results that may be generated.

Applicants wishing to submit updated or supplementary material in support of
their application can submit such material one time only no later than May 1,
2000.  The submission is limited to two single-sided pages, and 20 copies of
this should be submitted to Chief, Review Branch at the address below.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by NIDDK.  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 NIDDK in accordance with the review criteria stated below.  As part of the
initial merit review, all applications will receive a written critique and may
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 Diabetes and Digestive and Kidney Diseases 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, reviewer 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.

o Significance: Do the scientific projects address important problems? 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 the fields?

o Approach: Will the technology resources significantly improve progress made
by the projects.  Are the conceptual framework, design, methods, and analysis 
adequately developed, well-integrated, and appropriate to the aims of the
projects?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?  Are the applicant's plans for quality control of all 
materials adequate?  Is the bioinformatics support adequate?  Is the applicant
willing and able to participate actively in a collaborative program?  Will 
the applicant share resources and release data in a timely manner, and will
they train and educate other investigators in the use of these data and
materials?

o Innovation: Do the 5-10 representative projects employ novel concepts,
approaches, or methods?  Do the projects challenge existing paradigms or
develop new methodologies or technologies?  Are the 2-3 new pilot and
feasibility studies innovative?

o Investigator: Are the investigators appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the investigators?

o Environment: Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed technologies 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 be asked to examine how the scientific
projects will benefit from the new technologies, and how this will further
NIDDK programmatic interests.

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o 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 to the proposed
research.

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

AWARD CRITERIA

The anticipated date of award is September 30, 2000.

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, including program relevance of the
hypothesis-driven scientific projects that will be aided by the advanced
technology;

o Total cost of the project.

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:

Robert A. Star, M.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone: (301) 594-7715
FAX: (301) 480-3510
E-mail: StarR@extra.niddk.nih.gov

Philip F. Smith, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda MD 20892-6600
Telephone: (301) 594-8816
FAX: (301) 480-3503
E-mail:   ps56z@nih.gov

Jose Serrano, M.D., Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Dr MSC 6600
Bethesda MD 20892-6600
Telephone:     (301) 594-8871
FAX: (301) 480-8300
E-mail:SerranoJ@extra.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Donna Huggins
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone: (301) 594-8848 
FAX: 301-480-3504
E-mail: HugginsD@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847, 93.848, and 93.849.  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 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 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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