Inflammation plays a major role in vascular diseases such as atherosclerosis, vein graft stenosis and proliferative restenosis following angioplasty and stent placement. A key step that facilitates many of the pathogenic roles of SMCs is phenotype modulation of vascular smooth muscle cells (SMC). Phenotype modulation of SMC involves down-regulation of SMC-specific genes, such as smooth muscle myosin heavy chain and calponin. The overall goal of this proposal is to define targetable mechanisms by which inflammatory mediators initiate SMC de-differentiation. The central hypothesis of this proposal is that activation of STAT-1 by inflammatory mediators is a necessary step for the development of advanced atherosclerotic lesions in vivo. To test these hypotheses, we propose two specific aims.
Specific Aim 1 : Test the hypothesis that the transcriptional factor STAT-1 promotes the development of atherosclerosis in ApoE-deficient mice.
Specific Aim 2 : Determine the role of OSM in the development of advanced atherosclerosis in ApoE- deficient mice. This proposed work will elucidate the role of an important biological factor, OSM, in the evolution of the atherosclerosis. It will also identify STAT-1 pathway as a therapeutic target for controlling pathological vascular remodeling.

Public Health Relevance

Occlusion of blood vessels is a common feature of many vascular diseases such as coronary artery bypass, angioplasty and atherosclerosis. Our research is aimed at understanding how blood vessels become occluded. In particular, we plan to investigate how inflammation acts to promote excessive growth and migration of cells in the vessels wall. If the inflammatory process is unchecked, this would eventually cause narrowing of blood vessels. It is hoped that this research will lead to new therapies that will prevent atherosclerosis.

National Institute of Health (NIH)
Non-HHS Research Projects (I01)
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Cardiovascular Studies A (CARA)
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VA Puget Sound Healthcare System
United States
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