Mentor:  W. Robert Taylor, MD, PhD
Cardiology Division
Emory University School of Medicine
Room 308 WMB
404-727-8921
wtaylor@emory.edu

The overall goal of the laboratory is to study how various humoral and mechanical factors modulate vascular inflammatory responses as they pertain to the development of atherosclerosis, angiogenesis and hypertensive vascular disease.  Specifically, we study the effects of angiotensin II, advanced glycation end products and wall strain on these processes.

The specific projects underway include:

1) The Role of Angiotensin II in the Pathogenesis of atherosclerosis 

In this project we are focusing on the contribution of oxidative stress as a signaling mechanism in atherogenesis.  We are also exploring the functional contributions of specific candidate genes.

2) Mechanical Strain and Vascular Inflammation 

We have previously shown that when cyclic strain is applied to vascular smooth muscle cells, it induces the production of reactive oxygen species and an upregulation of proinflammatory genes.  We are currently studying the effects of cell phenotype on this response.  In addition, we are interested in the mechanical properties of vascular cells of different phenotypes.

3) Mechanisms of Angiogenesis

Angiogenesis is a complex process involving the growth and arterialization of new blood vessels.  We are currently using several animal models to define the roles of osteopontin (an extracellular matrix protein) and angiotensin II in this process.

4) Advanced Glycation Endproducts (AGEs) and Vascular Inflammation

 

AGEs are produced after extended periods of hyperglycemia (high blood sugar).  We have shown that AGE’s cause a proinflammatory response in the vessel wall.  We are currently looking the mechanisms of this response and the role of a specific receptor (RAGE) for AGE’s.

5) Endothelial Progenitor Cells and Vascular Disease

In this project we are developing new methodologies to isolate and culture human endothelial progenitor cells from the peripheral circulation.  These efforts are being coordinated with several clinical trials now underway at Emory.  In addition, we are integrating these studies with animal models of vascular disease to further explore the role of circulating endothelial progenitor cells in vascular repair and inflammation.

AIMS: The Atherosclerosis and Inflammatory Markers Study.  A randomized, double-blind, placebo-controlled, parallel group, comparative study of olmesartan, an angiotensin receptor blocker, in patients with established atherosclerosis.

Atherosclerosis is a mechanistically complex, multi-factorial disease process that culminates in lipid-laden, acellular lesions in the arterial wall.  Critical to our understanding of disease initiation and to our ultimate management of patients with pathologically advanced disease is an improved understanding of the most terminal cellular signaling pathways and the motive forces central to these pathways.  We, and others, have focused on the role of reactive oxygen species as modulators of inflammatory gene expression.  Pertinent to this proposal, are the observations that angiotensin II, acting through the type I receptor, activates NAD(P)H oxidase which subsequently results in increased production of reactive oxygen species.  These reactive oxygen species potently increase the expression of inflammatory gene products that have been suggested to be causative in initiating atherosclerotic lesion initiation.  The central thesis of this proposal is that angiotensin II activation through the AT₁ receptor is functionally important to atherosclerotic plaque initiation, progression, and rupture.  Furthermore, we propose that blockade of the AT₁ receptor will result in an anti-atherogenic response. This is a randomized, double-blind, placebo-controlled, two arm, parallel group study of the effect of olmesartan on circulating surrogate markers of atherosclerosis in patients with established atherosclerotic vascular disease of the lower extremities or Grade III or IV atherosclerosis of the aorta as defined by a screening transesophageal echocardiogram (TEE).  The primary endpoint for the determination of efficacy will be a composite of eight circulating surrogate markers of atherosclerosis for vascular inflammation.  The surrogate markers of vascular inflammation to be used will include C-reactive protein, MCP-1, M-CSF, VCAM-1, TNF, IL-1, E-Selectin, and ICAM-1.

Problems? Broken Links? Questions? Please contact Dr. Taylor