Role of MP-HBEGF-EGFR signaling for inflammatory action of oxidized phospholipids

描述(由申请人提供)：这位K99/R00将支持候选人的职业目标，成为心血管疾病领域的研究人员，专注于动脉粥样硬化。应聘者过去有与细胞生物学和药理学相关的教育背景，主要是受体信号项目和简单的阵列分析。候选人目前是加州大学洛杉矶分校的博士后研究员，K99培训将在加州大学洛杉矶分校的导师朱迪思·A·贝林纳博士和共同导师阿尔登斯·J·卢西斯博士的指导下进行。大学系统配备了高生产力和支持性的研究设施，包括系统化的研究行为培训。大学管理系统对新调查人员的成功非常支持。伯林纳博士是一位开拓性的研究人员，他发现了氧化磷脂在血管炎症反应中的重要作用。她在免疫组织化学分析方面的经验将对拟议研究的成功非常重要。Lusis博士是系统遗传学领域的杰出研究人员，他的工作在识别控制动脉粥样硬化发展的遗传因素和新的信号通路方面发挥了重要作用。在K99培训阶段，候选人将经常与导师和共同导师会面。候选人还将每6个月与顾问委员会举行一次会议。在K99指导阶段，候选人将专注于掌握免疫组织化学和病变分析方法，这是当前实验室和相关核心实验室的一大优势。K99的另一个重要方面将是学习分析工具来分析高通量转录本和基因分型数据集；这些研究正在由Lusis小组的大量人员进行。在独立的R00阶段，候选人将主要专注于深入研究Ox-PAPC在内皮细胞中激活MP的机制，并通过系统遗传学方法对遗传因素和细胞通路的意义进行验证研究。这项拟议研究的主要目的是确定氧化磷脂(Ox-PAPC)激活这一炎症途径的近端事件。在目标1的这项研究中，候选人将利用血管内皮细胞的体外培养来确定Ox-PAPC诱导MPS激活的机制。在目标2中，候选者将确定在小鼠动脉粥样硬化模型中，该途径是否被激活以促进炎症和病变的形成。最后，在目标3中，将使用系统遗传学方法来识别控制血管内皮细胞近端炎症反应的遗传因素和新的途径。在这项研究中，候选人将使用从96名人类捐赠者分离的主动脉内皮细胞的转录和基因分型数据集，这些数据集和细胞目前都是可用的。在当前实验室的Mentor和Co-Mentor下的K99培训阶段显然填补了执行拟议项目的技术空白。培训阶段结束后，候选人将配备更多不同的工具和方法来研究心血管疾病，以便成功过渡到独立的R00阶段。 公共卫生相关性：本研究旨在寻找动脉粥样硬化等慢性血管炎症性疾病的预防和治疗靶点。主要目的是为了促进针对血管炎症关键步骤的试剂的开发，以延长人类，特别是老年人的预期寿命。氧化应激和脂类的氧化产物已被证明与心血管疾病的发展有关。这项研究将验证一种假设，即血管氧化应激产生的氧化磷脂将激活内皮细胞表面的金属蛋白酶，以促进炎症细胞因子的表达，从而导致血管内的慢性炎症条件。这些研究还有可能确定更多的治疗靶点，并确定增加动脉粥样硬化易感性的遗传因素。

DESCRIPTION (provided by applicant): This K99/R00 will support candidate's career goal to become a researcher in the area of cardiovascular disease with a focus on atherosclerosis. The candidate has past educational background related with cell biology and pharmacology mainly on receptor signaling projects, and simple array analysis. The candidate is currently a postdoctoral fellow at UCLA and the K99 training will be executed under mentor Dr. Judith A. Berliner and co-mentor Dr. Aldons J. Lusis at UCLA. The university system is well equipped with highly productive and supportive research facilities including systemized training of conduct of research. The university administrative system is very supportive for the success of new investigators. Dr. Berliner is a pioneering researcher who identified important roles of oxidized phospholipids in the vascular inflammatory responses. Her experience with analysis of immuno-histochemistry will be important to the success of the proposed studies. Dr. Lusis is an outstanding researcher in the field of systems genetics whose work has been important in identifying genetic factors and novel signaling pathways controlling the development of atherosclerosis. During this K99 training phase, the candidate will meet frequently with mentor and co-mentor. The candidate will also meet with advisory board committee every 6 months. During the K99 mentoring phase, the candidate will focus on mastering immuno-histochemistry and lesion analysis methods, which is one of big advantages of current lab and associated Core labs. Another important aspect of the K99 will be learning the analytical tools to do analyze high-throughput transcript and genotyping datasets; these studies are being performed by a large number of those in the Lusis group. During the independent R00 phase, the candidate will mainly focus on the in-depth mechanistic studies for MP activation by Ox-PAPC in the endothelial cells, and the validation study of the significance of the genetic factors and cellular pathways identified via systems genetics approach. The main goal of this proposed study is to define proximal events in oxidized phospholipid (Ox-PAPC) activation of this inflammatory pathway. In this study in Aim 1, candidate will identify the mechanism by which Ox-PAPC induces activation of the MPs using in vitro culture of endothelial cells. In Aim 2, candidate will determine if this pathway is activated for inflammation and lesion formation in mouse model of atherosclerosis. Finally, in Aim 3, a systems genetics approach will be used to identify genetic factors and novel pathways controlling proximal inflammatory responses in vascular endothelium. For this study the candidate will use transcript and genotyping data sets of the aortic endothelial cells isolated from 96 human donors which datasets and cells are currently available. The K99 training phase under mentor and co-mentor in the current lab clearly fill the technical gaps to execute the projects proposed. After the training phase, the candidate will be equipped with more diverse tools and approaches to study the cardiovascular disease for successful transit to the independent R00 phase. PUBLIC HEALTH RELEVANCE: This study is to find preventive and therapeutic targets for the chronic vascular inflammatory diseases like atherosclerosis. The primary aim is to contribute to the development of reagents targeting critical step of vascular inflammation to increase life expectancy of human population, especially for aged people. Oxidative stress and the oxidation products of lipids have been shown to be involved in the development of cardiovascular diseases. This study will test the hypothesis that the oxidized phospholipids produced by vascular oxidative stress will activate metalloproteinases on the endothelial cell surface for proinflammatory cytokine expression leading to chronic inflammatory conditions in the vessel. These studies also have the potential to identify additional therapeutic targets and identify genetic factors that increase susceptibility of atherosclerosis.