[Federal Register Volume 70, Number 54 (Tuesday, March 22, 2005)]
[Notices]
[Page 14475]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-5565]



[[Page 14475]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Heart, Lung, and Blood Institute (NHLBI); Opportunity 
for a Cooperative Research and Development Agreement (CRADA) To 
Identify Small Molecule Inhibitors of Human Macrophage Cholesterol 
Accumulation for Therapy of Atherosclerotic Cardiovascular Diseases

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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SUMMARY: Macrophage cholesterol accumulation in blood vessels leads to 
the development of atherosclerotic plaques, the cause of most heart 
attacks and strokes. Recently, research from Dr. Howard Kruth, head of 
the Experimental Atherosclerosis Section of NHLBI has elucidated a 
novel mechanism of receptor-independent macrophage cholesterol 
accumulation\1,2\. In this pathway, human macrophages take up low-
density lipoprotein (LDL), the main carrier of blood cholesterol, by 
fluid-phase endocytosis, an uptake pathway that can be activated in 
macrophages. Activated macrophages show greatly stimulated uptake of 
fluid and LDL contained in the fluid through macropinocytosis, a fluid-
phase endocytic uptake pathway unique to macrophages. This mechanism of 
LDL uptake and macrophage cholesterol accumulation does not depend on 
binding of LDL to receptors. Macrophage macropinocytosis of LDL 
produces levels of cholesterol accumulation similar to that observed 
for macrophages isolated from atherosclerotic plaques, something that 
does not occur when human macrophages take up LDL by receptor-mediated 
mechanisms in these macrophages.
    The NHLBI is seeking CRADA collaborators to work with investigators 
in the Experimental Atherosclerosis Section of NHLBI to identify 
inhibitors of this cholesterol uptake pathway. The collaborator will 
provide high throughput screening capabilities coupled with small 
molecule and/or siRNA libraries of test compounds, or other 
methodologies to identify potential inhibitors of this pathway. A cell-
based screening assay that will have predictive value with human 
macrophages will be developed jointly by the NHLBI investigators and 
the collaborator based on published and unpublished research findings 
of the NHLBI investigators. The goal of this collaboration will be to 
identify compounds that selectively inhibit macrophage macropinocytosis 
and consequently macrophage uptake of LDL and cholesterol accumulation. 
Compounds identified will be further tested in a suitable animal model 
of atherosclerosis to determine their effect on macrophage cholesterol 
accumulation and atherosclerotic plaque development. Macropinocytosis 
also mediates entry of microorganisms such as HIV into macrophages. 
Thus, discovery of macropinocytosis inhibitors may be relevant not only 
to atherosclerosis treatment but also to certain infectious disease 
treatments.

References

    1. Kruth, H.S., Huang, W., Ishii, I., and Zhang, W.Y.: 
Macrophage foam cell formation with native low density lipoprotein. 
J. Biol. Chem. 277:34573-34580, 2002.
    2. Kruth, H.S., Jones, N.L., Huang, W., Zhao, B., Ishii, I., 
Chang, J., Combs, C.A. Malide, D., and Zhang, W.Y.: Macropinocytosis 
is the endocytic pathway that mediates macrophage foam cell 
formation with native LDL. J. Biol. Chem. 280:2352-2360, 2005.

    Contact: Inquiries concerning this CRADA opportunity should be 
directed to Ms. Peg Koelble, Technology Transfer Specialist, Office of 
Technology Transfer and Development, NHLBI, NIH; 6705 Rockledge Drive, 
Suite 6018, MSC 7992; Bethesda, Maryland 20892-7992, Telephone: 301-
594-4095; Fax: 301-594-3080; E-mail: [email protected]. Inquires 
must be received no later than 60 days after March 22, 2005.

    Dated: March 11, 2005.
Dr. Carl Roth,
Associated Director for Scientific Program Operations, National Heart, 
Lung, and Blood Institute.
[FR Doc. 05-5565 Filed 3-21-05; 8:45 am]
BILLING CODE 4140-01-M