Role of alternatively spliced Tissue Factor in atherosclerosis

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DESCRIPTION (provided by applicant): The goal of this proposal is to foster Dr. Chiara Giannarelli's development as an independent clinical investigator in translational cardiovascular research. Dr. Giannarelli will use a panel of molecular tools to address biological questions with the objective of translating laboratory-based findings into potential healthcare strategies. The proposed studies will be conducted in the laboratories of the Cardiovascular Institute of the Mount Sinai School of Medicine (MSSM). Dr. Giannarelli proposes to undertake a structured program involving didactic courses and research experiences. The Candidate will be mentored by Drs. Valentin Fuster, Roger Hajjar and Juan Badimon. This triumvirate has a combined record of outstanding accomplishments in research and training. The Cardiovascular Research Program involves basic and translational research focused on the cellular and molecular pathways triggering the initiation, progression and rupture of atherosclerotic lesions. Recent findings suggest that increased neovascularization of atherosclerotic plaques is a critical process to lesion growth, instability, rupture and cardiovascular clinical manifestations. Therefore, the targeted inhibition of plaque angiogenesis is a potential novel therapeutic approach toward plaque stabilization and prevention of cardiovascular events. In preliminary experiments, the Candidate has profiled the biological activity of alternatively spliced Tissue factor (asTF) as a potential angiogenic factor with potential impact in atherosclerosis. The overall aim is to establish a relationship between asTF, and plaque neovascularization, growth and instability. In Specific Aim 1 the Candidate will establish the clinical relevance of asTF in promoting intraplaque neovascularization, plaque instability and cerebrovascular events in two cohorts of patients: 1) patients with clinically stable and 2) patients with clinically unstable carotid disease undergoing carotid endartherectomy. Specific Aim 2 will test the hypothesis that asTF is differently expressed in various cell types within atherosclerotic plaques from patients with stable or unstable carotid disease. The Candidate employs a panel of techniques, such as Laser Capture Microdissection and Proteomic Technologies to establish a molecular signature at the single cell level. In Specific Aim 3 the Candidate will study expression of asTF in monocyte sub-populations in patients with stable and unstable coronary and carotid disease. This proposal outlines a novel paradigm of atherosclerosis as an angiogenic-dependent disease in which neovascularization of plaque is intimately involved. Elucidating the role of asTF as novel pro-angiogenic factor and identifying novel pathway(s) relevant for neovascularization in human atherosclerotic disease could yield the discovery of novel biomarkers and therapeutic targets of plaque instability leading to clinical events.