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 disease.
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 of the
Experimental Atherosclerosis Section of NHLBI has elucidated a novel mechanism
of receptor-independent macrophage cholesterol accumulation1, 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NHLBI investigators and the collaborator based on published and unpublished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:
Ms. Peg Koelble, Telephone: 301-594-4095; Fax:
301-594-3080 E-mail; Koelblep@nhlbi.nih.gov.
National Heart, Lung, and Blood
Institute (NHLBI); Opportunity for a Cooperative Research and Development
Agreement (CRADA) to identify and explore epigenetic regulatory elements for
diagnostic and therapeutics purposes.
Summary:
The National Heart, Lung, and Blood Institute
(NHLBI) is seeking Cooperative Research and Development Agreement (CRADA)
collaborator (s) to work with investigators in the Laboratory of Molecular
Immunology (LMI) to identify epigenetic regulatory elements that may be
involved in the disease development of T and/or B cell leukemia/lymphoma and
other cancers via genome-wide analysis of acetylation islands using the
Genome-Wide Mapping Technique (GMAT). Representative disease-specific
acetylation islands will be explored for diagnostic and therapeutic purposes.
Supplementary Information:
Epigenetics play a critical role in cellular
development and cellular transformation in many pathogenic processes. For
example, many cancers are correlated with changes of their chromatin structure
and are sensitive to drugs that modulate the levels of histone acetylation.
Epigenetic regulation refers to the modification of chromatin including
posttranslational modification of histones, which does not involve change of
DNA sequences of target genes. NHLBI investigators have mapped the genome-wide
distribution of histone H3 acetylation in human T cells and discovered over
40,000 acetylation islands using a technique called GMAT. This tool combines
Chromatin immunoprecipitation (Chip) of hyper-acetylated histones, with Serial
Analysis of Gene Expression (SAGE). The acetylation islands are epigenetic
markers for transcriptional regulatory elements and chromatin controlling
elements. Changes of the acetylation islands may be correlated with early
development of T cell lymphoma or leukemia. Therefore, this discovery may be
applied to early diagnosis and/or treatment of these diseases.
The NHLBI is seeking capability statements from
parties interested in entering into a CRADA to identify, explore and further
develop epigenetic regulatory elements/acetylation islands for diagnostic and
therapeutic purposes. The role of the CRADA collaborator (s) will include, but
not be limited to, the following:
- The ability to collaborate with NHLBI on further
research and development of this technology. This ability can be demonstrated
through experience and expertise in this or related areas of technology
indicating the ability to contribute intellectually to on-going research and
development.
- To assist with obtaining specimen/tissues
(patient and normal controls) for the Genome-Wide analysis as diagnostic and
therapeutic markers.
- To assist in further developing the epigenetic
regulatory elements markers/acetylation islands as new targets for novel
drug-development strategies.
The collaborator may also be expected to contribute
financial support under this CRADA for personnel, supplies, travel, and
equipment to support these projects. The collaborator is also expected to
cooperate with the NHLBI in the timely publication of research results and to
accept the legal provisions and language of the CRADA with only minor
modifications, if any.
Contact:
Vincent Kolesnitchenko, Ph.D., Phone: (301)
594-4115; Fax: (301) 594-3080; E-mail: vk5q@nih.gov.
The NHLBI has applied for patents claiming the core
of the technology. Non-exclusive and/or exclusive licenses for these patents
covering core aspects of this project are available to interested parties.
Respondents interested in submitting a CRADA Proposal should be aware that it
may be necessary to secure a license to the above-mentioned patent rights in
order to commercialize products arising from a CRADA.
National
Heart, Lung, and Blood Institute (NHLBI): Opportunity for Cooperative Research
and Development Agreements (CRADAs) to develop therapeutic uses for the newly
identified cardiac precursor "spoc" cells
The National Heart Lung and Blood Institute is
seeking research statements from parties interested in entering into a
cooperative Research and Development Agreement (CRADA). The purpose of the
CRADA is to develop therapeutic uses for the newly identified cardiac precursor
cells named "spoc" cells. These cells are a previously unknown subpopulation of
stem cells in adult murine skeletal muscle that can be transformed into beating
cardiomyocytes in primary tissue culture. These cells are not satellite cells,
myofibroblasts or myoblasts or hematopoietic stem cells. A portion of these
marked freshly isolated spoc cells, injected into the tail vein of a mouse with
an acute myocardial infarct populates the infarct in 2 weeks time; by 3 months
they differentiate into cardiac myocytes in the region of the infarct. Spoc
cells can be used to isolate orthologue human cells that may be useful in
treating chronic and acute heart failure. These cells may also be used to
produce cell lines from transgenic animals with targeted genes that are
important to cardiac function. Such cell lines will be useful in high
throughput pharmaceutical screening projects.
Capability statements:
Prospective collaborators need only be interested in
pursuing a focused aspect of the potential applications.
- Expertise in genomics/proteomics and analysis.
- Expertise in animal models of heart disease.
- Expertise in high throughput drug screening
Contact: Vincent Kolesnitchenko, Ph.D. at (301)
402-5579 or via email at Kolesniv@nhlbi.nih.gov
National Heart, Lung, and Blood
Institute (NHLBI): Opportunity for Cooperative Research and Development
Agreements (CRADAs) to develop novel mechanical and biological treatments in
interventional cardiovascular medicine using x-ray fluoroscopy and real-time
magnetic resonance imaging
Summary:
The National Heart, Lung, and Blood Institute
(NHLBI) of the National Institutes of Health (NIH) announces the opportunity
for Cooperative Research and Development Agreements (CRADAs) to develop novel
mechanical and biological treatments in interventional cardiovascular medicine
using x-ray fluoroscopy and real-time magnetic resonance imaging. The NHLBI
seeks potential Collaborators wishing to provide expertise in (1) novel
biological treatments for cardiovascular disease, including adult-derived stem
cell and cardiovascular progenitor cells, (2) novel agents for therapeutic
angiogenesis for myocardial or peripheral artery applications, (3) novel
mechanisms of drug, gene, or cell delivery to the myocardium or skeletal muscle
to treat manifestations of coronary or peripheral artery atherosclerosis, and
(4) intravascular devices for real-time magnetic resonance imaging-guided
treatments including but not limited to angioplasty balloons, recanalization
systems, percutaneous cardiac valves, stents, endografts, and bypass
grafts.
The NHLBI seeks capability statements from parties
interested in entering into a potential CRADA to manufacture, prototype, and
test the above-specified agents or devices leading to early clinical testing
and development. Collaborator applicants developing capability statements may
also include proposals to provide funding for possible commercial uses of
interest to the Collaborator. The availability of private sector support may
increase the feasibility of particular aspects of the final design, but the
primary criterion for selecting potential collaborators is the scientific merit
of proposals for developing a plan to identify novel putative therapeutic
agents and devices.
The NHLBI can provide extensive preclinical and
clinical support in the development of Collaborator deliverables, including
animal experiments, advanced x-ray fluoroscopic and magnetic resonance imaging
laboratories, and investigations conducted in the Warren G. Magnuson Clinical
Center at the Bethesda campus of the National Institutes of Health.
The control of clinical trials shall reside entirely
with the Institute and the scientific participants of the trial. In the event
that any adverse effects are encountered which, for legal or ethical reasons,
may require communication with the US Food and Drug Administration, the
relevant collaborating institutions will be notified. Neither the conduct of
the trial nor the results should be represented as an NHLBI endorsement of the
agent, drug, or device under study.
Contact:
Peg Koelble at 301-594-4095 or via email at
koelblep@nhlbi.nih.gov
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