The goal of this clinician scientist career development award is to facilitate my transition into an independent clinician-scientist with advanced knowledge and capacity with a niche addressing the critical role of matricellular interactions on pathologic remodeling of arteries. My training program comprises a mentored research plan with guidance from an integrated mentoring team with a mentor, Hanjoong Jo, PhD;two co- mentors: Allan Kirk MD, PhD;Bob Taylor MD, PhD;and two external advisors: Don Giddens, PhD (Georgia Institute of Technology);Scott Berceli, MD, PhD (University of Florida). Stiffened arteries independently increase patient mortality, and arterial stiffness initiates and accelerates the development of atherosclerosis. As a clinically active vascular surgeon with a PhD in cell biology, I have identified the development of treatment strategies for arterial stiffness as a significant clinical need for my patients. I have recently identified that disturbed flow promotes arterial stiffening in healthy mice. Preliminary data has identified thrombospondin-1 (THBS-1) as a clinically modifiable target of arterial stiffening in response to disturbed flow. This proposal determines the role of THBS-1 in arterial stiffness. My central hypothesis is that disturbed flow increases EC expression of THBS-1, which promotes arterial stiffness via TGF-? dependent and independent pathways. This project will identify and test the molecular mechanisms involved in arterial stiffness with sophisticated in vitro and in vivo models of disturbed flow. I ill focus this work on identifying the endothelial cell response to disturbed flow and the subsequent changes in vascular wall biology that lead to arterial stiffening utilizing cutting edge techniques with gain and loss of function testing. Importantly the pathways identified will be strategically inhibited to decrease arterial stiffening. This work will provide the protected time and resources necessary to generate important scientific contributions in this field and build my translational research laboratory for a sustainable career in patient-directed scientific investigation.
Arterial stiffness is a modifiable intermediary step in the initiation and progression of atherosclerosis. The biological and physiological cause of arterial stiffness and the signaling mechanisms involved are not well understood. I have demonstrated a novel role for disturbed flow on arterial stiffness and have preliminary evidence supporting the role of thrombospondin-1 (THBS-1) in this process. This clinician scientist career development proposal aims to identify and test in vitro and in vivo the molecular targets controlled by THBS-1 that lead to arterial stiffness. The protected time and mentorship availed to me by this award will develop my scientific skills in and knowledge of biomechanics and advanced molecular techniques to develop and integrate sophisticated biomechanical models of disturbed flow for testing key components of matricellular interactions in arterial stiffening.
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