HDL modulation of vascular smooth muscle cell chemokine expression and proliferation.Excessive unregulated smooth muscle cell (SMC) proliferation is a major cause of early graft/stent failure. In vitro studies have found the reconstituted HDL (rHDL) inhibits the expression of several key chemokines that have been implicated in SMC proliferation. The in vitro studies will then be extended to investigate the effect of HDL in mouse vein graft and stent models – specifically looking at the effects on SMCs.
The role of chemokine receptor CCR7 in HDL-induced regression of atherosclerosis.CCR7 is known to play an important role in plaque regression by directing the emigration of plaque macrophages, but its relationship with HDL is currently unknown. In vitro studies will determine if HDL can regulate CCR7 expression and if so to understand the mechanism by which this occurs. Through collaboration with the Westmead hospital, we will investigate the emigration of plaque macrophages in vivo using the “mac-green” transgenic mouse, which has fluorescent macrophages that will be tracked following treatment with HDL. Understanding the mechanisms that trigger plaque macrophage emigration and plaque regression is potentially very valuable. When patients present to clinic, atherosclerosis is already at an advanced stage. Plaque regression then becomes the primary goal.
HDL and Angiogenesis.
In collaboration with Dr Martin Ng, Head of the Translational Research Group, we are currently investigating the effect of HDL on the regulation of new blood vessel formation (angiogenesis). This is an NHMRC funded project that involves extensive in vitro studies and three distinct mouse models of angiogenesis including: myocardial infarction, atherosclerosis and cancer.
Differential Regulation of Angiogenesis by Chemokines.
Although in is its early stages, we are starting to investigate the importance of specific chemokines and chemokine classes in a host of inflammatory-driven angiogenic diseases. This project is using viral gene transfer technology to over-express novel proteins that inhibit specific chemokines in mouse models of endothelial injury/repair, advanced plaque development and cancer. Ultimately we aim to identify and develop chemokine agonists that can be used clinically to prevent inflammatory-driven angiogenic disease.
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