Proteomic Studies of MMP Profiles in Stroke Thrombolysis

描述（由申请人提供）： 这是一个K23指导的以患者为导向的研究职业发展奖的申请，题为：中风溶栓中MMP谱的蛋白质组学研究。候选人建议使用蛋白质组学技术研究基质金属蛋白酶（MMPs）在急性脑局灶性缺血溶栓结局中的机制，最终目标是优化患者选择，使急性卒中治疗更安全，更有效。我们推测MMP-9通过触发重要的下游细胞-细胞和细胞-基质信号传导机制而促进tPA相关损伤。本研究的主要目的是：1）在过表达MMP-9的人内皮细胞培养物中研究MMP-9的潜在下游底物; 2）将MMP-9底物表征扩展到更复杂但更生理相关的血栓溶解的人血浆环境，从而鉴定MMP-9和其他重要候选蛋白酶的额外底物;和3）进行探索性研究以扩大对溶栓结果重要的蛋白酶的库，作为治疗的潜在靶点。候选人寻求以下方面的培训：1）蛋白质组学技术和生物信息学的基本原理，以分析人类样本和细胞培养物中的蛋白质组学数据; 2）局灶性缺血中溶栓相关不良后果的神经生物学; 3）先进的流行病学临床研究方法，以进一步开展以患者为导向的研究。拟议的研究计划，教学课程和导师和顾问的指导说明将确保候选人的职业发展成为一个独立的临床科学家。

DESCRIPTION (provided by applicant): This is an application for a K23- Mentored Patient-Oriented Research Career Development Award entitled: Proteomic Studies of MMP Profiles in Stroke Thrombolysis. The candidate proposes to use proteomic technology to investigate the mechanism of matrix metallo-proteinases (MMPs) in thrombolysis outcome of acute cerebral focal ischemia, with the ultimate goal of optimizing patient selection to make acute stroke treatment safer and more utilized. We hypothesize that MMP-9 contributes to tPA-related injuries by triggering important downstream cell-cell and cell-matrix signaling mechanisms. The primary goals of the proposed research are: 1) to investigate MMP-9's potential downstream substrates in human endothelial cell culture over-expressing MMP-9; 2) to expand MMP-9 substrate characterization to the more complex but more physiologically-relevant environment of thrombolysed human plasma, thereby identifying additional substrates of MMP-9 and of other important candidate proteases; and 3) to conduct exploratory studies to expand the repertoire of proteases important to thrombolysis outcome, as potential targets for therapy. The candidate seeks training in: 1) proteomic techniques and the basic principles of bioinformatics, to analyze proteomic data in human samples and cell cultures; 2) the neurobiology of thrombolysis-related adverse outcome in focal ischemia; 3) advanced epidemiological clinical research methods, to further patient-oriented research. The proposed research plan, didactic courses, and tutorial instructions from mentors and advisors will ensure the career development of the candidate into an independent clinician scientist.