CALL FOR ASSAY PROPOSALS FOR THE NINDS HIGH THROUGHPUT DRUG SCREENING
SERVICE FACILITY
RELEASE DATE: March 05, 2004
NOTICE: NOT-NS-04-005
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov/)
The National Institute of Neurological Disorders and Stroke established
a high throughput drug screening (HTS) facility at Southern Research
Institute in Birmingham, Alabama in 2002. This facility was established
to provide an opportunity for neurodegeneration researchers with robust
and reproducible assays to have their assays tested against a
collection of 100,000 compounds in a high throughput setting. Working
closely with investigators, the facility adapts these assays into high
throughput formats and uses them to screen a collection of chemically
diverse compounds. The data from the screens is returned to the
contributing investigators for further evaluation. More information is
available at:
http://www.ninds.nih.gov/funding/areas/technology_development/HTS_Facility.htm.
The NINDS is now accepting proposals for new neurodegeneration-related
assays to be adapted and screened at the HTS facility. The types of
assays sought and instructions for applying to the program follow.
SCOPE
Assays proposed for this service should be relevant to mechanisms
associated with neurodegenerative diseases such as ALS, Parkinson’s
disease, Spinal Muscular Atrophy, Alzheimer’s disease or Huntington’s
disease and other triplet repeat disorders.
Many of the in vitro biological and disease assays currently used to
study the effects of specific compounds or genetic perturbations can be
adapted to high throughput formats. There are a number of
characteristics that make an assay suitable for high throughput
approaches. The assay must be robust, reproducible and have a readout
that is amenable to automated analysis. In addition, it must be
possible to miniaturize the assay to a 96-well or higher density
format. These features can be met by a broad range of assay types,
including enzymatic and biochemical assays, and assays in intact cells
or simple model organisms such as yeast or C. elegans. This
announcement seeks innovative assays for use in both mechanistic
studies and drug discovery programs, with an emphasis on biological
novelty and relevance to neurodegeneration. Appropriate assays include:
o Biochemical or cell-based assays of activity, behavior or interaction
of proteins and other molecules of interest.
o Assays of cellular or molecular phenotypes, viability or apoptosis.
o Assays using model organisms such as yeast or C. elegans.
o Assays involving mutant proteins linked to neurodegeneration or
neuroprotection.
o Modulation of expression of genes of interest, including effects on
transcription, translation or RNA splicing.
PROPOSAL CONTENT
Proposals should demonstrate reproducibility of the proposed assay in a
low-to-moderate throughput setting (e.g., 24-well format) and should be
feasible for adaptation to an automated, high-throughput screening
approach. For example, it should be possible to reduce the assay to a
96-well format and the assay should have a simple readout.
Demonstration of feasibility for HTS must include:
o Use of reagents and readouts that can be used in an automated HTS
environment. However, please note that the NINDS HTS facility does not
currently have high throughput imaging capability.
o Demonstration of highly predictable and reproducible responses to
pharmacological standards or other control conditions, including
acceptable signal-to-noise and signal-to-background ratios, and a
favorable Z value in a 96-well or higher density format.
In addition, it is desirable to demonstrate the selectivity and
reproducibility of response of the assay to a small but diverse
collection of a few hundred compounds, such a collection of FDA
approved drugs or other bioactive molecules.
There must also be a clear plan for confirming, evaluating the
significance of, and prioritizing the hits obtained in a primary high
throughput screen. This plan should be feasible for the evaluation of a
few hundred hit compounds that may be identified in a primary HTS
effort. This plan should include feasible counter screens and secondary
screens for confirming hits and eliminating artifacts.
The overall goals of the screening project should be well defined and
clearly presented. This discussion should include the expected use of
the compounds in a follow-up research program, either in the context of
biological research or therapeutics development. Plans for achieving
these goals, such as evaluating and optimizing the compounds for in
vivo testing, should be presented with enough detail to allow an
evaluation of overall feasibility and completeness.
ASSAY AUTOMATION AND SCREENING AT SOUTHERN RESEARCH
Assays accepted for screening at Southern Research will be developed
for automated screening in close collaboration with scientists at the
facility. Investigators will be required to visit the facility to
transfer the assay technique and to oversee pilot screens and
interpretation of pilot data. These activities are likely to require at
least two visits to the facility in Birmingham for at least one week at
a time.
Assays will be screened against a collection of approximately 100,000
public domain compounds. This collection consists of the 50,000
compound CNS-Set from Chembridge (http://www.chembridge.com), the MicroSource
Discovery Systems (http://www.msdiscovery.com) Spectrum Collection of 2000 FDA
approved and bioactive compounds and natural products, and a set of
50,000 compounds selected for chemical diversity from Tripos
(http://www.tripos.com).
Assays will be screened against this collection and the hits will be
subjected to reproducibility and dose-response testing. Investigators
will be given access to the entire data set from the screens as well as
the names and sources of the reproducibly active compounds that are
identified.
Unless otherwise negotiated before screening is begun, all intellectual
property that results from the assay development and screening will
reside with the contributing investigator. The Material Transfer
Agreement can be viewed at
http://www.ninds.nih.gov/funding/technology_development/HTS_Facility.htm.
COST ESTIMATION
It is NOT necessary to provide a detailed estimation of the cost of
developing and screening the assay. However, you must list the cost of
any non-standard reagents that must be purchased to conduct the
specific assay, such as antibodies, unusual media additives, viral
preparations, etc. These costs should be calculated for a single well
of a 96-well plate assuming a reaction volume of 200ul. You do NOT need
to calculate the cost of standard buffers, media, serum, etc., or the
cost of plates or other materials associated with cell culture or
screening.
MECHANISM OF SUPPORT
NINDS will cover the costs of assay automation and screening through a
contract with Southern Research. This will include the cost of travel
of investigators to the facility to convey specifics of assay design
and interpretation to scientists at Southern Research. Investigators
will receive no additional support through this mechanism.
Investigators are encouraged to apply for support for characterizing
the results of their screens through alternative NIH funding
mechanisms. Early stage characterization of hit compounds may be
appropriate for the R21 Exploratory/Developmental Grants Mechanism
(http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) or, for
therapeutically directed projects, PAR-02-138, NINDS
Exploratory/Developmental Projects in Translational Research
(http://grants.nih.gov/grants/guide/pa-files/PAR-02-138.html).
ELIGIBLE INSTITUTIONS
You may submit a proposal if your institution has any of the following
characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic institutions/organizations
HOW TO APPLY
Submission of proposals should be made electronically. Send an Email
message to HTSassays@ninds.nih.gov with the PI’s name (last name, first
name) on the Subject line. Include the following sections in an
attached file in MSWord, WordPerfect of PDF format:
o A cover page citing this NOTICE and including the title of the assay,
PI name, and address, phone and email information for the PI.
o An abstract.
o A proposal, limited to 5 pages, describing the assay, feasibility for
adaptation to HTS, mechanisms for validating hits from screening and
plans for use of the screening results.
REVIEW PROCEDURE
Applications appropriate to this solicitation will be reviewed by the
NINDS HTS Facility Steering Committee. This committee includes
scientists from academia, industry and the NINDS.
Review criteria will include:
o significance of the disease model for neurodegeneration
o novelty of the assay approach and research plan for use of the
compounds
o technical merit of the approach
o feasibility of adapting the assay to HTS format
o quality of the plan for evaluating the compounds identified by HTS
o quality of the statement of goals for use of identified compounds
either as research tools or for drug discovery
SELECTION CRITERIA
NINDS will select three to five assays per year to be screened at the
NINDS facility. Criteria for the selection of individual assays will
include:
o Scientific merit (as determined by the Steering Committee)
o Programmatic Priorities of NINDS
o Capacity of NINDS Facility
Receipt deadlines: April 2, 2004
June 1, 2004
Future deadlines will be announced in separate notices.
INQUIRIES
Dr. Jill Heemskerk
Program Director, Technology Development
National Institute of Neurological Disorders and Stroke, NIH
6001 Executive Boulevard, Room 2229
Bethesda, MD 20892
Phone: 301-496-1779
Email (preferred): jill_heemskerk@ninds.nih.gov
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