INTEGRATED GENOMICS TECHNOLOGIES

Release Date:  December 23, 1998

RFA:  RR-99-003

P.T.

National Center for Research Resources
National Human Genome Research Institute
National Institute of General Medical Sciences

Application Receipt Date:  February 23, 1999

PURPOSE

This Request for Applications (RFA) targets new, innovative, multidisciplinary
efforts to develop integrated genomics technologies, which will lead to the
biologists' tools of five or more years hence. The resulting highly integrated
technologies will be capable of high-speed serial or highly parallel analyses at
a sensitivity level capable of single-cell genomics analysis.  Such technologies
will enable new levels of understanding of cellular processes and will, for
example, permit development of highly specific drugs through screening against
in vivo cellular processes.  Development of new ex vivo analytical capabilities
will permit high throughput analysis of cellular/organelle constituents; single-
cell protein and nucleic acid sequencing, including characterization of
phosphorylation and methylation states; and single-cell genome expression
analysis.  Similarly, new in vivo analytical and methodological capabilities will
permit: characterization of protein interactions, including protein-protein,
protein-nucleic acid, protein-ligand interactions in single cells; in vivo
protein and nucleic acid sequencing; the biosynthetic production and self-
assembly of intracellular sensors and probes; and single-molecule detection in
single cells.

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 RFA, Integrated Genomics Technologies,
is related to several of the priority areas.  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).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and nonprofit
organizations, public or 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

Support for this RFA is through the NIH Research Project Grant (R01) mechanism. 
Applicants for R01 awards must receive permission from the NCRR prior to the
submission of an application requesting more than $500,000 in direct costs per
year for any year of the proposed study.

Awards will be administered under NIH grants policy as stated in the NIH Grants
Policy Statement, issued October 1, 1998
(http://grants.nih.gov/grants/policy/nihgps/).

FUNDS AVAILABLE

It is expected that four to eight awards will be made in FY99, and $4 million
will be designated for this purpose.  The number of awards will be dependent upon
receipt of a sufficient number and diversity of applications with high scientific
merit.

RESEARCH OBJECTIVES

A recent Integrated Genomics Technologies Workshop (October 15 and 16, 1998; the
workshop report will soon be uploaded to http://www.ncrr.nih.gov), sponsored by
the NCRR with the involvement of other NIH Institutes, the Department of Energy,
and the National Science Foundation, identified the grand challenge of fully
characterizing the genomics/proteomics of the intact living cell as the basis for
the identification of critical enabling technology development needs in this
area.

Contemporary genome sequencing and expression studies have suggested the
feasibility of our understanding the information encoded in the genome in the
context of the cell's protein world.  At the same time these studies have
indicated large gaps in our understanding of the protein constituents of the
cell, their local environment, and the quantitative details of the intracellular
protein-protein, protein-macromolecule, and protein-small molecule interactions--
which together define the material, energetic, and informational flows of the
living cell.

Recent developments in optical imaging, particularly quantitative fluorescence
microscopy; ultra-small volume sampling and analysis; incorporation of optically
useful probes, such as green fluorescent protein into cellular constituents;
combinations of photobleaching and imaging; and optical approaches to determining
the rates and equilibria of intracellular processes clearly indicate the enormous
potential of in vivo single cell studies for our understanding of cell
physiology, as well as the remaining substantial difficulties.

Biologists need tools capable of analyzing the genomic and proteomic information
of the living single cell. The quantitation, localization, and identification of
proteins within the cell, as well as full characterization of intracellular
interactions involving proteins in their structural, catalytic, and control
roles, will be essential for development of a comprehensive and integrative view
of cell physiology.  Furthermore, development of highly specific drugs must
ultimately involve screening against in vivo cellular processes.  Thus, the
envisioned technology development will enable the application of profoundly
powerful combinatorial approaches to understanding and regulating the interior
world of the cell, as well as characterizing the cell-physiological consequences
of rare phenotypes--particularly those associated with disease.

New ex vivo and in vivo measurement capabilities are needed for the quantitative
study of the intact cell's physiology.  Ex vivo analytical needs include single-
cell, high-throughput characterization of proteins, including their
identification, local concentration, and sequence, as well as characterization
of protein-protein and protein-small molecule interactions.  Such needs may be
approached through the development of new or significantly enhanced broad-based
integrated analytical platforms (MS, micro-NMR, and micro/nanofabricated high
sensitivity, high throughput devices).  No limitation on the nature of such
integrated devices should be construed from the examples provided.  In vivo
single-cell analytical needs include: approaches to single-molecule detection;
quantitation of rates and equilibria of protein-protein interactions; nucleic
acid and protein sequencing and identification; intracellular sensing; and
measures of whole cell and regional dynamical processes, including diffusion,
transport, and trafficking.  Specific examples of technology development related
to these analytical needs may include: new screens, extensions of photon
correlation spectroscopy, new near-field and surface plasmon resonance approaches
to subcellular spectroscopy, continued development of non-linear
spectroscopy/microscopy, achievement of single-cell NMR, approaches to the
analysis of the propagation of small perturbations from equilibrium, and
evanescent wave approaches to localization.  Many of the analytical needs have
no obvious current technology upon which to draw, suggesting that entirely new
technologies must be developed.

It is expected that such long-term systematic technology development efforts will
involve interdisciplinary teams engaging expertise in such areas as nano- and
microfabrication, engineering, laser applications, optics, molecular biology,
separation science, chemistry, physics, mathematics, and sensors.  The resulting
highly integrated technologies will be capable of high-speed serial or highly
parallel analyses at a sensitivity level capable of single-cell genomics
analysis.

Applications responsive to this RFA will propose development of new innovative
technologies in the context of genomics analysis.  This RFA does not seek
incremental improvements in specific analytical methods.  Instead, it seeks
broadly conceived multidisciplinary approaches to clearly defined genomics
analytical needs.  To be useful to the biologist of the future, devices must be
highly integrated, involving cell selection, separations methods,
analysis/detection, and output.  While an application need not involve all
aspects of an integrated high throughput device, it is necessary to utilize this
context in describing the significance and innovation of the proposed research.

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 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 has been published in the Federal Register of March 20, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number
11, March 18, 1994.

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

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 clear and compelling 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.

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 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 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 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.

The completed original application and three legible copies must be sent or
delivered 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)

Two additional copies of the application must also be sent to:

Office of Review
National Center for Research Resources
6705 Rockledge Drive, Room 6018 þ MSC 7965
Bethesda, MD 20892-7965
Bethesda, MD 20817 (for express/courier service)

Applications must be received by the application receipt date listed in the
heading of this RFA.  If an application is received after the application receipt
date, it will be returned to the applicant without review.

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
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 by the CSR for completeness and by
NCRR for responsiveness.  Incomplete and/or non-responsive applications will be
returned to the applicant without review.  Applications that are complete and
responsive will be reviewed for scientific and technical merit and the documented
ability of the investigators to meet the RESEARCH OBJECTIVES of this RFA by an
initial review group convened by the NCRR Office of Review, in accordance with
the standard NIH peer review procedures.  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
Advisory Research Resources Council.

REVIEW CRITERIA

Any response to this RFA must place the proposed integrated genomics technology
development into the broader context of genomics research.

o  Significance:  Does this study address an important problem?  Does the
proposed technology development have the potential of initiating paradigm shifts
in analysis of biological systems? 

o  Innovative aspects of the technology development plan: Does the project employ
novel concepts, approaches, or methods?  Are the aims original and innovative? 
Does the project challenge existing paradigms in developing new methodologies or
techniques?  It is not a requirement that the proposed studies be hypothesis
driven.

o  Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate to the aims of the
project?  Is the approach multi-disciplinary?  Does the applicant acknowledge
potential problem areas and consider alternative tactics?

o  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 investigator and other researchers (if any)?  For programs involving
integrating multidisciplinary efforts, the review committee will consider the
care with which the overall program is integrated and the detailed plans for
implementation of a comprehensive program.

o  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?

o  For those applications that propose collaborative efforts between several
applicants, additional factors to be considered during review would include the
efficacy of the collaboration, the commitment of the participants to the
collaboration, the design and responsibilities of the coordinating center and the
cost effectiveness of the collaborative effort.

o  Where appropriate, the adequacy of assurances detailing the proposed means for
(a) safeguarding human or animal subjects and/or (b) protecting against or
minimizing any adverse effect on the environment.

o  Adequacy of plans to include both genders, minorities, and children and their
subgroups as appropriate for the scientific goals of the research.

In addition, the review committee will evaluate the appropriateness of the
proposed budget and duration in relation to the proposed research.

Schedule

Application Receipt Date:  February 23, 1999
NCRR Committee Review:     June/July 1999
Council Review:            September 1999
Earliest Funding:          September 1999

AWARD CRITERIA

The anticipated date of award is September 30, 1999.  The factors that will be
used to make award decisions include:

o  Scientific and technical merit as determined by peer review,
o  Availability of funds, and
o  Programmatic priorities, such as balance among scientific areas.

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:

Karl A. Koehler, Ph.D. 
Biomedical Technology
National Center for Research Resources
6705 Rockledge Drive, Room 6160, MSC 7965
Bethesda, MD  20892-7965
Telephone: (301) 435-0755
FAX: (301) 480-3659
Email:  Karlk@ep.ncrr.nih.gov

Or send an email inquiry to:
BTAdir@ep.ncrr.nih.gov

Jeffery A. Schloss, Ph.D.
Technology Development Coordination
National Human Genome Research Institute
Building 38A, Room 614
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  jeff_schloss@nih.gov

James Cassatt, Ph.D.
CCB Division
National Institute of General Medical Sciences
45 Center Drive
Bethesda, MD  20892-6200
Telephone: (301) 594-0533
FAX: (301) 480-2004
Email:  Jc12b@NIH.GOV

Direct inquiries regarding fiscal matters to:

Ms. Judith Musgrave
Office of Grants Management
National Center for Research Resources
6705 Rockledge Drive, Room 6086, MSC 7965
Bethesda, MD 20892-7965
Telephone: (301) 435-0844
FAX: (301) 435-3777
Email:  jm133b@NIH.GOV

Ms. Jean M. Cahill
Grants Management Officer
National Human Genome Research Institute
38A Library Drive, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 402-0733
Email:  Jean_Cahill@nih.gov

Ms. Phyllis Finch
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive
Bethesda, MD  20892-6200
Telephone:  (301) 594-5135
Email:  pf21m@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.371.  Awards are made under authorization of the Public Health Service Act,
Title III, 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 74 or 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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