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, 14475 [05-5565]
Download as PDF
<![CDATA[
Federal Register / Vol. 70, No. 54 / Tuesday, March 22, 2005 / Notices
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
National Institutes of Health,
Public Health Service, HHS.
ACTION: Notice.
AGENCY:
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
accumulation1,2. In this pathway,
human macrophages take up lowdensity lipoprotein (LDL), the main
carrier of blood cholesterol, by fluidphase 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 receptormediated 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
VerDate jul<14>2003
15:26 Mar 21, 2005
Jkt 205001
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:
Koelblep@nhlbi.nih.gov. 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
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Substance Abuse and Mental Health
Services Administration
Agency Information Collection
Activities: Submission for OMB
Review; Comment Request
(SAMHSA) will publish a summary of
information collection requests under
OMB review, in compliance with the
Paperwork Reduction Act (44 U.S.C.
Chapter 35). To request a copy of these
documents, call the SAMHSA Reports
Clearance Officer on (240) 276–1243.
Government Performance and Results
Act Client/Participant Outcome (OMB
No. 0930–0208)—Revision
The mission of SAMHSA is to
improve the effectiveness and efficiency
of substance abuse and mental health
treatment and prevention services
across the United States. All of
SAMHSA’s activities are designed to
ultimately reduce the gap in the
availability of substance abuse and
mental health services and to improve
their effectiveness and efficiency.
Data currently are collected from all
SAMHSA best practices and targeted
capacity expansion grants and contracts
where client outcomes are to be
assessed at intake (or initial contact), 6
and 12 months post admission or postintervention. SAMHSA-funded projects
are required to submit these data as a
contingency of their award. The analysis
of the data will also help determine
whether the goal of reducing health and
social costs of drug use to the public is
being achieved.
The primary purpose of this data
collection activity is to meet the
reporting requirements of the
Government Performance and Results
Act (GPRA) by allowing SAMHSA to
quantify the effects and
accomplishments of SAMHSA
programs. In addition, the data will be
useful in addressing goals and
objectives outlined in ONDCP’s
Performance Measures of Effectiveness.
The revision of this data collection
affects only the Center for Substance
Abuse Treatment (CSAT). The proposed
revision will modify the CSAT services
instrument to include new questions on
family characteristics, specific services
and social connectedness to align with
the SAMHSA Administrator’s seven
domains for national outcomes
measures. In addition, the data
collection time points will change to
intake, discharge, and 6 months post
admission.
The following is the estimated annual
response burden for this collection.
Periodically, the Substance Abuse and
Mental Health Services Administration
PO 00000
Frm 00040
Fmt 4703
Sfmt 4703
14475
E:\FR\FM\22MRN1.SGM
22MRN1
]]>Agencies
[Federal Register Volume 70, Number 54 (Tuesday, March 22, 2005)]
[Notices]
[Page 14475]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-5565]
[[Page 14475]]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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: Koelblep@nhlbi.nih.gov. 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
