Proteomic Studies of MMP Profiles in Stroke Thrombolysis

描述(由申请人提供)： 这是一份K23指导的以患者为导向的研究职业发展奖的申请书，题为：中风溶栓中基质金属蛋白酶图谱的蛋白质组学研究。候选人建议利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疗效中的作用机制，最终目的是优化患者选择，使急性中风治疗更安全和更有效。我们假设，基质金属蛋白酶-9通过触发重要的下游细胞-细胞和细胞-基质信号机制而参与tPA相关的损伤。拟议研究的主要目标是：1)研究人内皮细胞培养中过表达基质金属蛋白酶-9的S潜在下游底物；2)将基质金属蛋白酶-9的底物特性扩展到更复杂但更具生理相关性的人血浆环境，从而确定更多的基质金属蛋白酶-9及其他重要候选蛋白酶的底物；以及3)进行探索性研究，以扩大对溶栓结果至关重要的蛋白酶谱，作为潜在的治疗靶点。应聘者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中的蛋白质组数据；2)局灶性脑缺血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，以进一步以患者为中心的研究。建议的研究计划、教学课程以及来自导师和顾问的指导说明将确保候选人的职业发展成为一名独立的临床科学家。

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.