MINIATURIZATION OF ASSAYS FOR PHENOTYPING SMALL ANIMAL MODELS SBIR/STTR)

Release Date:  February 14, 2000

NOTICE:  DK-00-002

National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

The purpose of this Notice, relating to the SBIR/STTR program, is to 
emphasize and encourage the development of miniaturized assays that 
can be used to measure metabolites, ions, hormones and other signals 
in very small volumes of tissue.  Microassays developed pursuant to 
this Notice should be useful for longitudinal metabolic or 
physiologic studies in small animal (mouse) models of disease, or in 
human subjects.  This research topic is of special interest to the 
NIDDK and is identified in the NIH Omnibus Solicitation for SBIR 
Grant Applications found at 
http://grants.nih.gov/grants/funding/sbirsttr1/index.htm

A collaborative approach among academic and industry leaders is 
strongly encouraged in order to facilitate development and 
distribution of important technology.  Through the Small Business 
Innovative Research (SBIR) and Small Business Technology Transfer 
(STTR) mechanisms (R41/R43/R42/R44), small businesses can receive 
funding for early phase development of innovative technologies and 
proof of principle studies leading toward commercialization of these 
technologies.  The solicitations are available electronically 
through the NIH, Office of Extramural Research "Small Business 
Funding Opportunities" home page located at 
http://grants.nih.gov/grants/funding/sbir.htm

Background

New chip and similar technologies will soon allow high-throughput 
screening of the genetic code, the expressed genes and their protein 
products, both in the laboratory and in the clinic.  Transgenic 
methodologies have already resulted in the production of an enormous 
variety of new mouse strains engineered specifically to study 
particular genes or diseases.  We can look forward to an enhanced 
ability to produce an even larger range of mice, and to identify a 
large number of genetic variants in people.  In order to take full 
advantage of these new genetic tools to study metabolic diseases 
such as diabetes and obesity, it is important to improve the 
methodologies used to determine the metabolic and physiologic 
phenotypes of these animals and the metabolic outcome of genetic 
variation in people.  New assays should be noninvasive or require 
very small volumes of tissue or employ implantable devices for 
continuous monitoring.  This Notice calls for SBIR and STTR 
applications to develop assays for standard markers of metabolic and 
physiologic function that use minute volumes of tissue or body 
fluids and can be easily used in a variety of clinical and 
laboratory settings.

A large number of techniques are currently used to characterize 
metabolism and physiology in people and in larger animals.  These 
include the measurement in plasma of other body fluids of 
metabolites such as glucose and fatty acids, hormones such as 
insulin and glucagon, ions like calcium and sodium, cytokines and 
other signaling molecules, and various proteins.  These measurements 
are used alone or in combination with infused radioactive or stable 
isotopes.  We can also measure an enormous number of signaling and 
storage molecules, enzyme activities, etc., in biopsied tissue.  
Noninvasive imaging and spectroscopic techniques are used to monitor 
physiologic phenomena like blood flow and oxygenation, and other 
parameters of organ function.  PET, NMR, absorption and fluorescence 
spectroscopy are increasingly used to measure metabolic parameters 
in living animals and people, and can now be used to interrogate 
brain function.

Many of the existing techniques for characterizing metabolism and 
physiology can also be used in transgenic mouse models, but must be 
scaled down for use in tiny animals or small volumes of tissue.  
These techniques should use a minimum of blood or other tissues or 
be as noninvasive as possible so that repeated measures can be made 
over the life of a single animal.  Appropriate reagents, such as 
mouse antibodies, must be used.  In order to meet a need for 
widespread use by researchers from many different disciplines, the 
techniques should be inexpensive, easy to use, robust, and allow for 
the rapid screening of a large number of animals.
Many of the same considerations apply to the production of 
microassays that can be used in the clinical setting.  For instance, 
time and money could be saved and risk to the patient reduced if a 
hormone profile, viral or other pathogen load, or metabolite or ion 
concentrations could be easily measured using a drop of blood from a 
finger stick instead of many ml drawn from a vein.

Scope

The objective of this initiative is to support small companies and 
partnerships between companies and academic institutions in the 
development of commercially available miniaturized assays for use in 
the clinic, in metabolic research on humans, or in metabolic and 
physiologic characterization of transgenic mouse models.  These 
assays should ideally be inexpensive, reproducible, and either 
automated or easily implemented in a variety of disease models and 
laboratory settings.  A very broad range of metabolic products, 
signaling molecules, hormones, pathogens, enzymes and other 
proteins, and physiologic measurements of blood flow, metabolic 
fluxes, or other indices of organ function are appropriate research 
goals.  Although it is impossible to foresee all assays that will be 
needed to phenotype very specialized animal models, it is possible 
to establish a set of standardized assays that can be used in a very 
large variety of mouse models.  Examples are:

?  Glucose, lactate, common fatty acids and amino acids, ions such as 
calcium, potassium, and sodium, and oxygen and carbon dioxide 
partial pressures measured in very small plasma volumes; 

?  Measurement of many hormone concentrations simultaneously in the 
same tissue sample;  

?  Easy measurement of cytokine profiles;

?  Miniaturization of assays for enzyme activity for use in small 
tissue samples;

?  Imaging or spectroscopic techniques for high-throughput or 
noninvasive measures of tissue composition, blood flow, oxygenation, 
metabolic flux, substrate uptake, or organ function in mice.  
Especially important would be miniaturized, inexpensive equipment 
for imaging in mice;

?  Miniaturization of currently available, widely used automated 
assays for use in mice, or standardization of currently used 
specialized assays in forms that are inexpensive and easily 
implemented;

?  Miniaturization of currently available assays for use in human 
needle biopsy tissue specimens.

Mechanism of Support

The mechanism of support will be SBIR/STTR grants.  Although the 
average Phase I award for SBIR/STTR grants is approximately $100,000 
in total costs for a 6-month project period, NIDDK recognizes that 
applications responsive to this Notice might require more funds and 
a somewhat longer duration to accomplish the objectives of a Phase I 
project.  Applications should fully justify all proposed budgets and 
project periods.  Applicants are encouraged to use the Fast-Track 
mechanism, which allows Phase I and II applications to be submitted 
and reviewed together.  This eliminates the chance of a funding gap 
between the two phases of the project 
http://grants.nih.gov/grants/funding/sbirsttr1/6method.htm

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or 
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Maren R. Laughlin, Ph.D.
Director, Metabolism Program
Division of Diabetes, Endocrinology and Metabolic Diseases
NIDDK
Building 45, Room 5AN-24J
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
(301) 594-8802 phone
(301) 480-3503 FAX
maren.laughlin@nih.gov

Direct inquiries regarding fiscal matters to:

Mary Kay Rosenberg
Grants Management Specialist
NIDDK
Building 45, Room 6AS-49D
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
(301) 594-8891 phone
(301) 480-3504 
RosenbergM@extra.niddk.nih.gov


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