Endothelial Cell Mechanical Dysfunction in Early Stage Atherosclerosis

动脉粥样硬化早期的内皮细胞机械功能障碍

• 批准号: 9332188
• 负责人: Robert Steward
• 金额: $ 14.74万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9332188
• 关键词: Adherens Junction; Aerospace Engineering; Agonist; Arterial Fatty Streak; Atherosclerosis; Award; Biochemical; Biological Sciences; Biomedical Research; Blood Vessels; Book Chapters; Books; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Career Choice; Cell-Cell Adhesion; Cells; Cities; Data; Deposition; Endothelial Cells; Endothelium; Engineering; Ensure; Environment; Esters; Event; Florida; Foam Cells; Functional disorder; Funding; Future; Generations; Goals; Health Sciences; Immunology; In Vitro; Inflammation; Inflammatory; Injury; Intercellular Junctions; Interdisciplinary Study; International; Investigation; Knowledge; Lead; Leukocytes; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; Mammalian Cell; Measures; Mechanics; Medical; Medical Research; Medical center; Medicine; Mentors; Methods; Molecular Biology; Morphology; Paper; Pathogenesis; Pediatric Hospitals; Penetration; Peripheral; Permeability; Pharmacology; Play; Prevention; Process; Protein Family; Proteins; Publications; Publishing; Recruitment Activity; Reporting; Research; Research Institute; Research Personnel; Resistance; Role; Scientist; Site; Tea; Testing; Text; Tight Junctions; Time; Training; Universities; Very low density lipoprotein; Veterans; authority; base; bench to bedside; career; cholesterol control; college; cytokine; design; experience; experimental study; fluid flow; insight; macrophage; mechanical drive; mechanical force; monolayer; novel; novel strategies; novel therapeutics; oxidation; oxidized low density lipoprotein; prevent; professor; programs; public health relevance; response; skills; success; technology development

 DESCRIPTION (provided by applicant): The PI is an assistant professor and the first dual hire between the Department of Mechanical and Aerospace Engineering and College of Medicine at the University of Central Florida. His background is in mechanical engineering and his research experiences have primarily focused on the development of technologies to mechanically stimulate mammalian cells and investigation of associated morphological responses. A total of thirteen publications have been produced thus far, including five first-author publications, two book chapters, and one equal contribution. The PI is highly motivated become an independent investigator in the cardiovascular field, but the PI's past research to date has only been peripherally related to the field. Furthermore, the PI believes the best treatment for many cardiovascular diseases is prevention at its earliest stages. Early stage atherosclerosis, for example, involves the entry and accumulation of low density lipoprotein (LDL) within the endothelium and leukocyte transmigration across the endothelium eventually yielding foam cells, the precursors of atherosclerotic plaques 1-9. Present during each of the previously mentioned processes within the endothelial monolayer are innate cell-cell adhesion forces10-15, whose roles and underlying biomolecular components have yet to be discovered. Therefore, the proposed award will investigate the hypothesis that decreased cell-cell junction activity decreases cell-cell adhesion forces, prompting increased LDL penetration and increased leukocyte transmigration across the endothelium under disturbed fluid flow. To test the above hypothesis a training plan is proposed that will allow the PI to develop expertise essential to the completion of this project in the following fields; molecular biology, atherosclerosis, and immunology. To ensure that the PI gains these skill sets the PI will be mentored by Dr. Sampath Parthasarathy. Dr. Parthasarathy is an internationally recognized authority on atherosclerosis. He has published over 150 papers on the topic (out of over 250) and has written a text book on "Modified Lipoproteins in the Pathogenesis of Atherosclerosis". His mentoring and guidance will therefore be invaluable to the success of the PI. Furthermore, the PI's training will take place in UCF's College of Medicine, which is located on Orlando's Medical City campus. This health and life sciences research park also includes the Sanford-Burnham Medical Research Institute, Nemour's Children Hospital, and Veterans Affairs Orlando Medical Center, providing an ideal biomedical research environment for the PI. Successful completion of this training award will put the PI on a career path to achieve the following goals; 1) to become an established investigator in the cardiovascular field and 2) obtain preliminary data to apply for future RO1 funding. In addition, the very long term career goal of the PI is to establish a multidisciplinary research tea that will consist of other independent investigators who are engineers, clinicians, and scientists to apply for PO1 funding and establish a research program in cardiovascular pathology aimed at developing novel bench-to-bedside cardiovascular therapies that would consist of treating cardiovascular disease at the cellular level.

 描述（由申请人提供）：PI是一名助理教授，也是中央佛罗里达大学机械与航空航天工程系和医学院之间的第一个双聘教授。他的背景是机械工程，他的研究经验主要集中在机械刺激哺乳动物细胞的技术开发和相关形态反应的研究。到目前为止，共出版了13种出版物，其中包括5种第一作者出版物，两种书籍章节和一种同等贡献。主要研究者非常有动力成为心血管领域的独立研究者，但主要研究者过去的研究迄今为止仅与该领域相关。此外，PI认为许多心血管疾病的最佳治疗方法是在早期阶段进行预防。例如，早期动脉粥样硬化涉及低密度脂蛋白（LDL）在内皮内的进入和积累以及白细胞穿过内皮的迁移，最终产生泡沫细胞，即动脉粥样硬化斑块的前体1-9。在内皮细胞单层内的每个前述过程中存在的是先天性细胞-细胞粘附力10 -15，其作用和潜在的生物分子组分尚未被发现。因此，拟议的奖项将调查的假设，减少细胞-细胞连接活性降低细胞-细胞粘附力，促使增加LDL渗透和增加白细胞穿越内皮细胞扰动流体流动。 为了检验上述假设，提出了一项培训计划，该计划将使PI能够发展对 本项目在以下领域完成：分子生物学、动脉粥样硬化和免疫学。为了确保PI获得这些技能，PI将由Sampath Parthasarathy博士指导。Parthasarathy博士是国际公认的动脉粥样硬化权威。他发表了150多篇关于该主题的论文（超过250篇），并撰写了一本关于“动脉粥样硬化发病机制中的修饰脂蛋白”的教科书。因此，他的指导和指导对PI的成功将是无价的。此外，PI的培训将在 UCF的医学院，位于奥兰多的医疗城校园。这个健康和生命科学研究园区还包括Sanford-Burnham医学研究所，Nemour儿童医院和退伍军人事务部奥兰多医疗中心，为PI提供理想的生物医学研究环境。成功完成该培训奖励将使PI走上职业道路，以实现以下目标：1）成为心血管领域的知名研究者; 2）获得初步数据，以申请未来的RO 1资助。此外，PI的长期职业目标是建立一个多学科研究小组，由工程师、临床医生和科学家等其他独立研究者组成，以申请PO 1资助，并建立一个心血管病理学研究项目，旨在开发新型的从实验室到床边的心血管疗法，包括在细胞水平治疗心血管疾病。