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

MP-HBEGF-EGFR 信号传导在氧化磷脂炎症作用中的作用

• 批准号: 8189619
• 负责人: Sangderk Lee
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8189619
• 关键词: Animal Model; Area; Atherosclerosis; Binding; Blood Vessels; CCL2 gene; Cardiovascular Diseases; Cell surface; Cells; Cellular biology; Cholesterol; Chronic; Cysteine; Data Set; Development; Disease; Educational Background; Endothelial Cells; Endothelium; Epidermal Growth Factor Receptor; Event; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Histocytochemistry; Human; IL8 gene; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knockout Mice; Learning; Lesion; Life Expectancy; Lipids; Mediating; Membrane Microdomains; Mentors; Metalloproteases; Methods; Modification; Mus; Oxidative Stress; Pathway Analysis; Pathway interactions; Pharmacology; Phase; Phospholipids; Population; Postdoctoral Fellow; Predisposition; Preventive; Reagent; Receptor Activation; Receptor Signaling; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Structure; System; Testing; Training; Transcript; Universities; Variant; Vascular Endothelial Cell; Vascular Endothelium; Vascular System; Weight; Work; aged; analytical tool; career; cytokine; experience; heparin-binding EGF-like growth factor; in vivo; macrophage; meetings; mouse model; novel; oxidation; oxidized phosphatidyl choline; research facility; response; success; therapeutic target; tool; validation studies; vascular inflammation

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.

描述（由申请人提供）：此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，重点是动脉粥样硬化。具有细胞生物学和药理学相关的教育背景，主要研究受体信号项目和简单的阵列分析。该候选人目前是加州大学洛杉矶分校的博士后，K99培训将在加州大学洛杉矶分校的导师Judith a . Berliner博士和共同导师Aldons J. Lusis博士指导下进行。大学系统配备了高效和支持性的研究设施，包括系统的研究行为培训。大学的行政管理系统非常支持新研究者的成功。Berliner博士是一位开拓性的研究人员，他确定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至关重要。Lusis博士是系统遗传学领域的杰出研究人员，他的工作在确定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。在这个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个月与顾问委员会会面一次。在K99指导阶段，候选人将重点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的另一个重要方面是学习分析工具来分析高通量转录物和基因分型数据集；这些研究是由Lusis小组的许多人进行的。在独立R00期，候选人将主要专注于内皮细胞中Ox-PAPC活化MP的深入机制研究，以及通过系统遗传学方法确定的遗传因素和细胞通路的意义验证研究。本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Aim 1的这项研究中，候选人将通过体外培养内皮细胞来确定Ox-PAPC诱导MPs活化的机制。在Aim 2中，候选人将确定该途径是否在小鼠动脉粥样硬化模型中被激活炎症和病变形成。最后，在Aim 3中，系统遗传学方法将用于识别控制血管内皮近端炎症反应的遗传因素和新途径。在这项研究中，候选人将使用从96名人类供体中分离的主动脉内皮细胞的转录本和基因分型数据集，这些数据集和细胞目前是可用的。在导师和联合导师的指导下，K99培训阶段在当前的实验室中清楚地填补了执行所提议项目的技术空白。在培训阶段后，候选人将具备更多样化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。