PROBES AND INSTRUMENTS FOR MICRO-IMAGING THE BRAIN 

Release Date:  October 23, 1998

PA NUMBER: PA-99-007

P.T.

National Institute of Mental Health
National Institute on Deafness and Other Communication Disorders

PURPOSE

The National Institute of Mental Health (NIMH) and the National Institute on
Deafness and Other Communication Disorders (NIDCD) issue this Program
Announcement (PA) to invite grant applications for Small Business Innovation
Research (SBIR) projects on micro-imaging the brain and other parts of the
nervous system, with award duration and amounts greater than those routinely
allowed under the SBIR program. The NIMH and NIDCD encourage applications from
teams of investigators from commercial, academic and other sectors of the
research community.  Non-commercial partners, including those at colleges and
universities, may play important roles in SBIR-supported research, and may
receive substantial support for their efforts.

More specifically, this PA solicits SBIR grant applications that propose
research and development of tools and approaches to better image the structure
and function of molecules and subcellular elements of neurons and other cells
of the nervous system.  Of special interest are applications that propose
research and development of wholly novel approaches and tools, although
significant enhancements of those which already exist are also solicited. 
This initiative has two thrusts: novel probes to generate signals reflecting
processes and structures, and novel instruments (including software) with
which to detect and analyze those signals.  An individual application may
propose to focus on both probes and instruments, or on just one of these
areas.

It is expected that this initiative will require expertise from a variety of
disciplines, including neuroscience, biology, chemistry, physics, engineering,
biotechnology, and bioengineering.  Moreover, it is anticipated that these
types of expertise will be brought together in various combinations in
individual proposed projects.

This PA must be read in conjunction with the Omnibus Solicitation of the
Public Health Service (Omnibus Solicitation) for Phase I SBIR Grant
Applications (PHS 98-2) and the instructions for Phase II Grant Applications
revised March 1998.  All instructions and information in these documents also
apply to applications submitted in response to this PA except where otherwise
noted, below. 

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 PA, PROBES AND INSTRUMENTS FOR
MICRO-IMAGING THE BRAIN, is related to the priority area of mental health and
mental disorders and chronic diseases.  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

Eligibility requirements are described in the Omnibus Solicitation.

MECHANISM OF SUPPORT - PHASE I

Phase I applications in response to this PA will be funded as Phase I SBIR
Grants (R43) with modifications as described below. Responsibility for the
planning, direction, and execution of the proposed research will be solely
that of the applicant.  Applications for Phase I grants should be prepared
following the directions for Phase I SBIR applications as described in the
Omnibus Solicitation. The Omnibus Solicitation is available on the Internet
at: 
http://www.nih.gov/grants/funding/sbir1/sbir.htm

A limited number of hard copies of the Omnibus Solicitation are available
from:

PHS SBIR/STTR Solicitation Office
13685 Baltimore Avenue
Laurel, MD  20707-5096
Telephone:  (301) 206-9385
FAX:  (301) 206-9722
Email:  a2y@cu.nih.gov

o  Project Period and Amount of Award

Because the duration and cost of research developing novel agents and/or
instruments for studying cellular physiology and structure often exceeds that
routinely awarded for SBIR grants, NIMH and NIDCD will consider well-justified
Phase I applications under this PA with a project period up to two years and a
budget not to exceed a total cost of $400,000 (an average of $200,000 per
year).

o  Consultant and contractual costs

The total amount of all consultant costs and contractual costs normally may
not exceed 33% of the total costs requested for Phase I SBIR applications. 
Nevertheless, NIMH and NIDCD will consider well-justified Phase I applications
under this PA with greater than 33% contractual costs when additional costs
are necessary to support collaborative activities with academic institutions
or with other partners.

o  Page Limitations

The 25-page limitation for Phase I applications applies (see Omnibus
Solicitation).

MECHANISM OF SUPPORT - PHASE II

Phase II applications in response to this PA will be awarded as Phase II SBIR
grants (R44) with modifications as described below.  Phase II applications in
response to this PA will only be accepted as competing continuations of
previously funded NIH Phase I SBIR awards.  The previously funded Phase I
award need not have been awarded under this PA, but the Phase II proposal must
be a logical extension of the Phase I research.

Applications for Phase II awards should be prepared following the instructions
for NIH Phase II SBIR  applications in the Omnibus Solicitation.

o  Project Period and Amount of Award

Because the duration and cost of research developing novel agents and/or
instruments for studying cellular physiology and structure often exceeds that
routinely awarded for SBIR grants, NIMH and NIDCD will consider well-justified
Phase II applications under this PA with a project period up to three years
and a budget not to exceed $450,000 per year total cost.

o  Consultant and Contractual Costs

The total amount of all consultant costs and contractual costs normally may
not exceed 50% of the total costs requested for Phase II SBIR applications. 
Nevertheless, NIMH and NIDCD will consider well-justified Phase II
applications under this PA with greater than 50% contractual costs when
additional costs are necessary to support collaborative activities with
academic institutions or with other partners.

MECHANISM OF SUPPORT - FAST TRACK

The Fast Track initiative (described in the Omnibus Solicitation) is designed
to expedite the decision and award of SBIR Phase II funding for scientifically
meritorious applications for projects that have a high potential for
commercialization. 

Fast Track is a parallel review option available to those small business
concerns (applicant organizations) whose applications satisfy additional
criteria which enhance the probability of the projectþs commercial success;
those criteria are described in the Omnibus Solicitation.  Applications that
do not meet these criteria may be redirected for review through the standard
review procedures described in the Omnibus Solicitation.

Fast Track offers two major advantages: 1) concurrent submission and peer
review of both Phase I and Phase II projects and 2) minimal or no funding gap
between Phase I and Phase II.

SBIR applications are eligible for the Fast Track review process upon meeting
the criteria which are described in the Omnibus Solicitation.  Special aspects
of the Phase I and II components of applications submitted in response to this
PA, as described above, also apply to Phase I and II components of Fast Track
type applications submitted in response to this PA. 

MECHANISM OBJECTIVES

The SBIR program consists of the following three phases:

o  Phase I

The objective of Phase I is to establish the technical merit and feasibility
of proposed research or research and development efforts and to determine the
quality of performance of the small business grantee organization prior to
providing further federal support in Phase II.

o  Phase II

The objective of this phase is to continue the research or research and
development efforts initiated in Phase I.

o  Phase III

The objective of this phase, where appropriate, is for the small business
concern to pursue the commercialization of the results of the research or
research and development funded in Phases I and II.  Phase III occurs without
SBIR funding.

RESEARCH OBJECTIVES

Background 

This initiative has two thrusts:  novel probes to generate signals reflecting
processes and structures within cells of the nervous system, and novel
instruments (including software) with which to detect and analyze those
signals.  An individual application may propose to focus on both probes and
instruments, or on just one of these areas.

NOVEL PROBES:  An emerging area of scientific opportunity is the design and
use of probes to study structure and function at the molecular and subcellular
level in living cells.  Approaches and tools such as labels that attach to
specific peptide or nucleotide moieties, Fluorescent Resonance Energy
Transfer, Green Fluorescent Protein (and mutant color variants), and
genetically-engineered voltage or ion-sensitive fluorophores are making it
possible to begin to visualize not only the distribution of molecular species
in cells, but the manner in which they interact.

Research and development of these, and other such, technologies hold the
promise of providing scientists the capabilities to track the ebb and flow of
signal transduction cascades, protein-protein interactions, protein-nucleotide
interactions, movement of subcellular elements within cells, and other dynamic
events.  And, it appears that as such tools are elaborated and further
studied, they will permit such observations to be quantitative and made in
real time.  Finally, bioengineering individual probes that are detectable by
multiple modalities, e.g., electron microscopy, fluorescent microscopy and
spectroscopy, magnetic resonance imaging) would add great value by allowing
independent lines of scientific inquiry to converge on the same cellular
process and/or structure as indicated by the multimodal probe.

This area of science and technology is poised for major advances, and these
advances would bring new levels of understanding of the molecular physiology
of nervous system cells, as well as the manner in which this physiology is
affected by disease, pharmacologic agents, development, etc. 

NOVEL INSTRUMENTS:  The signals generated by existing probes as well as probes
that are developed in response to this program announcement will, of course,
need to be detected and analyzed. In the last several years, a range of
technologies has been developed that permit better spatial resolution of
signals generated intrinsically and by probes, better capabilities for
understanding three dimensional structure, and better ways to following
molecular and cellular processes in the fourth dimension, time.

Imaging instruments at the cutting-edge of biology which are well positioned
for advances include, but are not limited to:  two/multi-photon laser
microscopy (for benign analysis of fluorophores or autofluorescence), magnetic
resonance micro-imaging (for cellular level imaging), magnetic resonance force
imaging (molecular level imaging), electron energy-loss spectroscopic imaging
(for analysis of elemental composition of specimens), cryoelectron microscopy
(three dimensional structural analysis of non-crystallized macromolecules),
and near field optical scanning microscopy (non-invasive "force" microscopy of
living cells).  An important aspect of such instrumentation is the software to
facilitate the acquisition, analysis and visualization of data by these
instruments.

By taking these, and other, tools to the next level of sophistication, and by
developing entirely new instruments and associated software, it should be
possible to begin to fill in the spatial resolution gap between that afforded
by X-ray crystallography and that possible with microscopy.  Moreover, it
should be possible to improve the ability to follow quantitatively changes and
movement of probes over time.

Research Topics

Examples of general research topics that would be considered responsive to
this PA are listed below.  This is not meant to be an exhaustive, exclusive or
delimiting set of topics, rather these merely represent illustrations of
projects that would be considered relevant to this PA.

o  Bioengineering of very small, sterically benign probes that can be
genetically linked to proteins that play important roles in cell function

o  Research, development and engineering of probes that can be detected with
both fluorescent microscopy and near field optical scanning microscopy to
report the rate of turnover of specific receptors or other membrane proteins

o  Research and development of probes that attach to specific sites on
proteins which are observable through light microscopy and magnetic resonance
micro-imaging.

o  Development of high speed multi-photon microscopy to track the movement,
and quantitate the amount of probes reporting intracellular signal
transduction processes

o  Research of instruments for spectral analyses of Fluorescent Resonance
Energy Transfer data generated by intracellular processes

o  Development of electronics and software to improve signal to noise ratios
in videomicroscopy 

o  Design and development of software to analyze and compare datasets from
imaging instruments.

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 that inclusion is
inappropriate with respect to the health of the subjects of 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 have been 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.

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

NIH POLICY AND GUIDELINES ON THE 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 is scientific or ethical reasons not to include them.  This
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://www.nih.gov/grants/guide/notice-files/not98-024.html

APPLICATION PROCEDURES

Applicants should follow the instructions for SBIR Phase I, Phase II, or Fast
Track submission with the modifications as noted in this PA.  Potential
applicants are strongly encouraged to contact program staff for pre-
application guidance and/or for more specific information on the research
topics described in this PA.

Mailing Instructions

For purposes of identification and processing, the title and number of this PA
must be shown in item 2 on the face page of the SBIR Phase I applications and
in item 1A of the face page of Phase II grant applications (i.e., "PROBES AND
INSTRUMENTS FOR MICRO-IMAGING THE BRAIN," PA-99-007).

Follow the mailing instructions in the Omnibus Solicitation for Phase I
applications.  Follow the mailing instructions in the Phase II application
package for Phase II applications.

REVIEW CONSIDERATIONS

Review Procedures

Applications will be assigned on the basis of established PHS referral
guidelines.  Upon receipt, applications will be reviewed for completeness by
the NIH Center for Scientific Review.  Incomplete applications will be
returned to the applicant without further consideration.

Applications will be reviewed for scientific and technical merit by study
sections of the Center for Scientific Review, NIH, in accordance with the
standard NIH peer review procedures. 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 appropriate national
advisory council.

Review Criteria

Review criteria are described in the Omnibus Solicitation.  The Phase I
application should specify clear, measurable goals (milestones) that should be
achieved prior to initiating Phase II.  Failure to provide clear, measurable
goals may be sufficient reason for the study section to judge the application
non-competitive.

Release of Grant Application Review Information

Following evaluation of grant applications by the study section but prior to
National Advisory Council or Board action, summary statements will be sent
automatically to principal investigators.  A "summary statement" documents the
evaluation of an application by the study section and conveys the groupþs
recommendations to the awarding component and its Council or Board. No one
other than the Principal Investigator may receive the summary statement and
evaluation rating.

AWARD CRITERIA

The following will be considered when making funding decisions:  quality of
the proposed project as determined by peer review, program balance among
research areas of the announcement, the availability of funds, and the
commercialization status where the small business concern has received more
than 15 Phase II awards in the prior five (5) fiscal years, if applicable (see
this application requirement under "Prior SBIR Phase II Awards" found in the
"Introduction and Application Instructions" portion of the Omnibus
Solicitation).

Applications will compete for available funds with all other favorably
recommended SBIR applications.  Note that applicants may achieve all Phase I
goals and milestones and still not receive Phase II funding.

INQUIRIES

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

Inquiries regarding programmatic issues may be directed to:

Michael F. Huerta, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 11-103
Rockville, MD  20857
Telephone:  (301) 443-3563
FAX:  (301) 423-1731
Email:  mhuerta@helix.nih.gov

Lynn E. Huerta, Ph.D.
Division of Human Communication
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400-C, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-3458
FAX:  (301) 402-6251
Email:  lynn_huerta@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Melinda Nelson
Grants Management Branch
National Institute of Child Health and Human Development
6000 Executive Boulevard, Room 8A17
Bethesda, MD  20892-7510
Telephone:  (301) 496-5481
FAX:  (301) 402-0915
Email:  nelsonm@hd01.nichd.nih.gov

Sharon Hunt
Grants Management Branch
National Institute on Deafness and Other Communication Disorders
6120 Executive Boulevard, Room 400-B, MSC 7180
Bethesda, MD  20892-7180
Telephone:  (301) 402-0909
FAX:  (301) 402-1758
Email:  sharon_hunt@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.242 (NIMH) and No. 93-173 (NIDCD).  Awards are made under authorization of
the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.  Awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy Statement
(April 1, 1994).

PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the nonuse of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.


Return to Volume Index

Return to NIH Guide Main Index


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


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