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Principal Investigator: Dr. Jun-Lin Guan
Contact Information: E-mail: jg19@cornell.edu
- Phone: 607-253-3586
Sponsor: NIH-University of California, San Diego
Grant Number: 2 R01 HL064382-06A1
Title: Mechanical and Molecular Bases of Endothelial Remodeling
Annual Direct Cost: $63,291
Project Period: 08/01/05-07/31/10
The shear stress due to blood flow is borne primarily by
endothelial cells (ECs) located at the interface between blood and vessel wall.
Atherosclerotic lesions are preferentially localized in regions such as
arterial branch points and local lumen expansions, where the ECs are subjected
to disturbed flow conditions, including flow reattachment, low shear stress
magnitude, high shear stress gradient, and little net direction of flow. The
ECs in these regions have different structural and functional characteristics
in comparison to those in the straight parts of the arterial tree, which are
exposed to pulsatile flow with a large net forward direction. Our Hypothesis is
that flows with a significant net direction cause adaptive changes in cell
morphology to reduce surface stress and alter molecular signaling, such that
the ECs can optimize their functions. In contrast, disturbed flows without a
significant net direction do not elicit the same adaptive effects on EC surface
stress distribution and lead to different spatial and temporal characteristics
of molecular signaling, structural remodeling, and mechanical properties, thus
resulting in distinct functional consequences such as vulnerability to
atherosclerosis. The following five Specific Aims are proposed to test our
hypothesis by using a combination of in vitro (first three Specific Aims), ex
vivo and in vivo approaches: (1) To determine the effects of different shear
flow patterns on surface stress and structural remodeling of ECs. (2) To
elucidate the interplays between EC remodeling and molecular signaling in
response to different shear flow patterns. (3) To elucidate the mechanisms by
which different shear flow patterns regulate EC proliferation and apoptosis.
(4) To establish the mechanisms by which different shear flow patterns regulate
EC remodeling, molecular signaling and proliferation/apoptosis in blood vessels
ex vivo. (5) To establish the mechanisms by which different shear flow patterns
regulate EC remodeling, molecular signaling and proliferation/apoptosis in
blood vessels in vivo. Dr. Shu Chien, in cooperation with Drs. Y.C. Fung, Juan
Lasheras and Roger Tsien at UCSD, will lead the projects for the studies under
all specific aims. Dr. Michael Sheetz at Columbia University will be
responsible for identifying the roles of membrane tension and cytoskeleton
affinity for cytoplasmic proteins in mechanotransduction. Dr. Jun-Lin Guan at
Cornell University will study the molecular mechanisms regulating EC functions,
especially in relation to KLF2 and FAK. The interdisciplinary research
conducted under this Bioengineering Research Partnership will elucidate the
mechanical and molecular bases of the differential adaptive changes of the ECs
in response to different flow patterns. The findings obtained from these
studies will advance our fundamental knowledge on mechanotransduction and
remodeling, thus providing the mechanistic basis for the development of novel
approaches for diagnosis and treatment of cardiovascular disorders.
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