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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