[Federal Register Volume 61, Number 30 (Tuesday, February 13, 1996)]
[Notices]
[Pages 5564-5565]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-3179]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health


National Heart, Lung, and Blood Institute; Opportunity for a 
Cooperative Research and Development Agreement (CRADA) for the 
Development of Lymphocyte ADP-Ribosyltransferase and its Corresponding 
Hydrolase as a Potential Target for Therapeutic Intervention in 
Diseases of the Immune System

AGENCY: Department of Health and Human Services, National Institutes of 
Health.

ACTION: Notice.

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SUMMARY: The National Heart, Lung, and Blood Institute (NHLBI), of the 
National Institutes of Health is seeking capability statements from 
parties interested in entering into a Cooperative Research and 
Development Agreement (CRADA) on the further characterization of 
lymphocyte ADP-ribosyltransferase as a potential target for therapeutic 
intervention in diseases of the immune system. This project is with the 
National Heart, Lung, and Blood Institute, Division of Intramural 
Research, Pulmonary-Critical Care Medicine Branch, located in Bethesda, 
Maryland.
    The goal is to use the respective strength of both partners in (1) 
identifying molecular targets of ADP-riboslylation in lymphocytes and 
muscle cells, and, (2) evaluating the potential use of this enzyme and 
its various substrates as targets of novel treatment modalities in 
certain diseases of the immune system and in hematological, pulmonary, 
and cardiac diseases.
    ADP-ribosylation is a post-translational modification of proteins, 
in which the ADP-ribose moiety of NAD is transferred to a protein 
acceptor. In the case of certain bacterial toxins (e.g. pertussis 
toxin, cholera toxin), ADP-ribosylation modifies hormone action on 
their human target cells and is the mechanism responsible for toxin 
action and, in large part, the pathogensis of disease. Human cells have 
endogenous ADP-ribosylation pathways: the pathways are composed of 
enzymes that place ADP-ribose on proteins, ADP-ribosyltransferases, 
which catalyze a reaction similar to the bacterial toxins, and enzymes 
that remove ADP-ribose, ADP-ribosylarginine hydrolases. Hence, ADP-
ribosylation may be reversible, with ADP-ribosyltransferases and ADP-
ribosylarginine hydrolases serving as components of a regulatory cycle.
    ADP-ribosyltransferases have been found in peripheral blood 
mononuclear cells and in skeletal and cardiac muscle. These enzymes 
have been cloned and are identical. The transferases, are linked to the 
cell surface through glycosylphosphatidylinositol (GPI)-anchors. In the 
muscle, they ADP-ribosylate the extracellular domain of an integrin and 
hence may participate in the regulation of cell-matrix interactions. 
Other data suggest that ADP-ribosylation may be involved in the 
regulation of cytotoxic lymphocyte activity. The cell surface location 
of the transferases may facilitate their specific targeting by 
chemotherapeutic agents. In particular, they may be targeted in 
diseases where lymphocytes are readily 

[[Page 5565]]
accessible (e.g., lymphocytic alveolitis amenable to inhalation 
therapy).
    It is anticipated that the commercial collaborator will participate 
in ongoing studies to determine whether modifying ADP-
ribosyltransferase activity and cell surface ADP-ribosylation can 
affect the immune system (e.g., mononuclear cell function) and cardiac 
skeletal and muscle function, and hence the progression of some 
hematological, pulmonary, cardiac, and musculoskeletal diseases. It is 
expected that the collaborator will assist in the development of 
specific inhibitors. These would be focussed on the structure of known 
NAD-binding sites that participate in ADP-ribosylation reactions, 
taking into account the facts that a cell surface enzyme is being 
targeted and the enzyme is preferentially located on lymphocytes, and 
cardiac and skeletal muscle. In diseases of the pulmonary system 
characterized by lymphocytic infiltration, one route for selective 
targeting of the transferase may involve the use of inhalation 
therapies that minimize systemic toxicity. Collaborator may also be 
expected to contribute funding for supplies and personnel to support 
this project. The NHLBI has applied for patents, both domestic and 
foreign, claiming this core technology. Non-exclusive and/or exclusive 
licenses for these patents covering core aspects of this project are 
available to interested parties.
    Capability statements should be submitted to: Ms. Lili M. Portilla, 
Technology Transfer Specialist, National Institutes of Health, National 
Heart, Lung, and Blood Institute, Technology Transfer and 
Commercialization Team, 31 Center Drive MSC 2490, Room 31/5A48 
Bethesda, MD 20892-2490. Capability statements must be received by 
NHLBI 30 days after date of publication in the Federal Register.

    Dated: February 1, 1996
Claude Lenfant,
Director, NHLBI.
[FR Doc. 96-3179 Filed 2-12-96; 8:45 am]
BILLING CODE 4140-01-M