Role of alternatively spliced Tissue Factor in atherosclerosis

选择性剪接组织因子在动脉粥样硬化中的作用

基本信息

批准号：
8723269
负责人：
Chiara Giannarelli
金额：
$ 14.23万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723269
关键词：
Address Angiogenic Factor Area Arterial Fatty Streak Atherosclerosis Award Basic Science Biological Biological Markers Cardiovascular system Carotid Artery Plaques Carotid Endarterectomy Cell Separation Cells Classification Clinical Clinical Investigator Coagulation Process Coronary Coronary Arteriosclerosis Coronary heart disease Cytoplasmic Tail Development Disease Event Extracellular Domain Extramural Activities F3 gene Flow Cytometry Fostering Funding Future Gene Expression Gene Proteins Goals Growth Healthcare Human Immunohistochemistry Institutes Integrins Laboratories Lead Lesion Lipids Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Membrane Glycoproteins Mentors Molecular Molecular Profiling Molecular Target Pathway interactions Patients Phenotype Plasminogen Activator Inhibitor 1 Play Polymerase Chain Reaction Population Prevention Process Protein Isoforms Proteomics RNA Splicing Research Research Personnel Research Training Role Rupture Specimen Structure Surface Techniques Technology Testing Thromboplastin Translating Translational Research Transmembrane Domain Up-Regulation Vascular Endothelial Cell Vascular Endothelial Growth Factors Western Blotting acute coronary syndrome angiogenesis base cardiovascular risk factor cell type cerebrovascular clinically relevant cohort experience hypoxia inducible factor 1 laser capture microdissection macrophage medical schools monocyte neovascularization new therapeutic target novel novel therapeutic intervention programs protein expression research study therapeutic target tool

项目摘要

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.

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，目的是将实验室研究结果转化为潜在的医疗保健策略。拟议的研究将在西奈山医学院心血管研究所 (MSSM) 的实验室进行。 Giannarelli 博士建议开展一项涉及教学课程和研究经验的结构化项目。候选人将由博士指导。瓦伦丁·福斯特、罗杰·哈贾尔和胡安·巴迪蒙。这三巨头在研究和培训方面均取得了杰出成就。心血管研究计划涉及基础和转化研究，重点关注触发动脉粥样硬化病变发生、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形成的增加是病变生长、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，候选者已将选择性剪接组织因子 (asTF) 的生物活性描述为一种潜在的血管生成因子，对动脉粥样硬化具有潜在影响。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 在促进两组患者斑块内新生血管形成、斑块不稳定性和脑血管事件方面的临床相关性：1) 临床稳定的患者和 2) 接受颈动脉内膜切除术的临床不稳定颈动脉疾病患者。具体目标 2 将检验以下假设：asTF 在稳定或不稳定颈动脉疾病患者的动脉粥样硬化斑块内的各种细胞类型中表达不同。候选人采用激光捕获显微切割和蛋白质组学技术等一系列技术来建立单细胞水平的分子特征。在具体目标 3 中，考生将研究稳定和不稳定冠状动脉和颈动脉疾病患者的单核细胞亚群中 asTF 的表达。该提案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例，其中斑块的新生血管形成密切相关。阐明 asTF 作为新型促血管生成因子的作用并确定与人类动脉粥样硬化疾病中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的新型生物标志物和治疗靶点。