[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
