Role of alternatively spliced Tissue Factor in atherosclerosis

描述（由申请人提供）：本提案的目标是促进Chiara Giannarelli博士作为转化心血管研究的独立临床研究者的发展。Giannarelli博士将使用一组分子工具来解决生物学问题，目的是将基于实验室的发现转化为潜在的医疗保健策略。拟定研究将在西奈山医学院心血管研究所（MSSM）的实验室进行。Giannarelli博士建议进行一个结构化的计划，包括教学课程和研究经验。候选人将由Valentin Fuster、Roger Hajjar和Juan Badimon博士指导。这三巨头在研究和培训方面都有着杰出的成就。心血管研究计划涉及基础和转化研究，重点是触发动脉粥样硬化病变的启动，进展和破裂的细胞和分子途径。最近的研究结果表明，动脉粥样硬化斑块新生血管的增加是病变生长、不稳定、破裂和心血管临床表现的关键过程。因此，靶向抑制斑块血管生成是稳定斑块和预防心血管事件的潜在新治疗方法。在初步实验中，候选人已经将选择性剪接组织因子（asTF）的生物活性描述为潜在的血管生成因子，对动脉粥样硬化有潜在影响。总体目标是建立asTF与斑块新生血管形成、生长和不稳定性之间的关系。在具体目标1中，候选人将确定asTF在两个患者队列中促进斑块内新生血管形成、斑块不稳定性和脑血管事件的临床相关性：1）接受颈动脉内膜切除术的临床稳定型颈动脉疾病患者和2）接受颈动脉内膜切除术的临床不稳定型颈动脉疾病患者。具体目标2将检验asTF在稳定或不稳定颈动脉疾病患者动脉粥样硬化斑块内的各种细胞类型中不同表达的假设。候选人采用一组技术，如激光捕获显微切割和蛋白质组学技术，以建立单细胞水平的分子特征。在具体目标3中，候选人将研究稳定和不稳定冠状动脉和颈动脉疾病患者单核细胞亚群中asTF的表达。这一建议概述了动脉粥样硬化作为一种血管生成依赖性疾病的新范式，其中斑块的新血管形成密切相关。阐明asTF作为新的促血管生成因子的作用并鉴定与人类动脉粥样硬化疾病中的新血管形成相关的新途径可以发现导致临床事件的斑块不稳定性的新生物标志物和治疗靶点。

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.