Vascular Smooth Muscle Lysyl Oxidase Mediated Increase in Vessel Stiffness and its Effect on Rho-Kinase Mechanosensors: A Novel Mechanism of Atherosclerosis in Chronic Kidney Disease?

血管平滑肌赖氨酰氧化酶介导的血管僵硬度增加及其对 Rho 激酶机械传感器的影响：慢性肾病动脉粥样硬化的新机制？

• 批准号: 9332185
• 负责人: Rajesh Mohandas
• 金额: $ 15.27万
• 依托单位: UNIVERSITY OF 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/9332185
• 关键词: Advisory Committees; Alpha Cell; Animal Model; Aorta; Apolipoprotein E; Arteriographies; Atherosclerosis; Attenuated; Basic Science; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Proliferation; Cells; Chronic Kidney Failure; Clinical; Clinical Sciences; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen; Custom; Data; Development; Disease; Elastin; Engineering; Ensure; Environment; Enzymes; Event; Extracellular Matrix; Fellowship; Florida; Functional disorder; Grant; Health; Heart Diseases; Histopathology; Hydroxylysine; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro; International; Journals; Kidney Diseases; Knock-out; Length; Lysine; Measures; Mediating; Mediator of activation protein; Mentors; Molecular; Molecular Biology; Mus; Muscle Cells; Nephrectomy; Paper; Patients; Phenotype; Physicians; Physiology; Placebos; Prevention; Protein Isoforms; Protein Kinase; Protein-Lysine 6-Oxidase; Publishing; ROCK1 gene; Randomized; Recruitment Activity; Regulation; Research; Research Personnel; Rho-associated kinase; Role; Scientist; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Staining method; Stains; Technology; Testing; Training; Training Programs; United States National Institutes of Health; Universities; Up-Regulation; Vascular Diseases; Vascular Proliferation; Vascular Smooth Muscle; arterial stiffness; base; career development; cell motility; crosslink; design; endothelial dysfunction; genome editing; in vivo; in vivo Model; inhibitor/antagonist; innovation; liquid chromatography mass spectrometry; meetings; migration; mortality; mouse model; novel; polyacrylamide gels; pressure; prevent; professor; response; sham surgery; success; tenure track; tool; vascular contributions

Cardiovascular disease is the leading cause of death in Chronic Kidney Disease (CKD). Arterial stiffness is increased in CKD, correlates with mortality, and is thought to be a key mediator of adverse cardiovascular events. However, the molecular mechanisms by which CKD causes increased arterial stiffness and how stiffness accelerates atherosclerosis is uncertain. Our novel preliminary data demonstrates that lysyl oxidase (LOX), an enzyme that crosslinks collagen and elastin, is up-regulated in vascular smooth muscle cells in CKD and could contribute to increased arterial stiffness. The increased stiffness in turn activates the rho-kinase isoform, ROCK1 which has been shown to increase migration and proliferation of vascular smooth muscle cells. These data suggest that atherosclerosis might be a consequence of stiffness and points to a primary, vascular smooth muscle cell dysfunction in CKD. The specific aims of this proposal are to (1) characterize the role of lysyl oxidase in mediating arterial stiffness in CKD, (2) define the role of ROCK1 in the regulation of smooth muscle migration and proliferation in response to stiffness, and (3) evaluate the role of lysyl oxidase and rho kinase in atherosclerosis in a CKD model in vivo. The successful completion of these specific aims will define the potential of targeting vessel stiffness as a potential mechanism to prevent vascular dysfunction of CKD. Vascular smooth muscle cells could be a new target for the prevention of cardiovascular complications in CKD patients and the basis for developing an independent line of research for Dr. Mohandas. Dr. Mohandas has completed a NIH sponsored T32 research fellowship, published 13 first or senior author papers and presented at national and international scientific meetings. He was recruited as a `Tenure Track Assistant Professor' at the University of Florida because of his outstanding track record and potential to be an independent physician scientist. To this end, a comprehensive but focused training program has been designed to enhance Dr. Mohandas' training in vascular physiology and molecular biology. This includes hands-on training in animal models of kidney disease, innovative genome editing tools, pressure arteriography, didactic coursework in cell signaling and vascular physiology, as well as seminars and journal clubs. Dr. Mark Segal, a highly regarded physician and expert in atherosclerosis and molecular biology, will serve as the candidate's mentor. An Advisory Committee has been assembled to aid the candidate in scientific and career development including Dr. Kirk Conrad (vascular physiology), Dr. Peter Sayeski (cell signaling), and Dr. Carl Pepine (experimental and clinical cardiovascular diseases). The outstanding environment of the University of Florida, rich in clinical and basic sciences, together with the scientific plan and comprehensive training program, will ensure the success of Dr. Mohandas as an independent investigator in the field of cardiovascular complications of kidney disease.

心血管疾病是慢性肾脏病(CKD)的主要死亡原因。动脉僵硬是 慢性肾脏病增加，与死亡率相关，被认为是不良心血管疾病的关键介质。 事件。然而，慢性肾脏病导致动脉僵硬增加的分子机制以及如何 僵硬加速动脉粥样硬化是不确定的。 我们新的初步数据表明，赖氨酰氧化酶(LOX)，一种使胶原和 弹性蛋白在慢性肾脏病血管平滑肌细胞中表达上调，可能是导致动脉粥样硬化的原因之一 僵硬。僵硬度的增加反过来激活了Rho-Kinase亚型ROCK1，已被证明 增加血管平滑肌细胞的迁移和增殖。这些数据表明动脉粥样硬化 可能是僵硬的结果，并提示CKD患者存在原发的血管平滑肌细胞功能障碍。 这项建议的具体目的是(1)表征赖氨酰氧化酶在调节动脉僵硬中的作用。 在慢性肾脏病中，(2)确定ROCK1在调控血管平滑肌迁移和增殖中的作用 对僵硬的反应，以及(3)评估赖氨酰氧化酶和Rho激酶在慢性肾脏病动脉粥样硬化中的作用 活体模型。这些具体目标的成功完成将确定目标舰艇的潜力 僵硬是预防慢性肾脏病血管功能障碍的潜在机制。血管平滑肌细胞 可作为CKD患者心血管并发症预防的新靶点和依据 为莫汉达斯博士开发一条独立的研究路线。 莫汉达斯博士完成了NIH赞助的T32研究奖学金，发表了13篇第一或高级作者 发表论文，并在国内和国际科学会议上发表。他被招募为‘Tenure Track’ 在佛罗里达大学担任助理教授，因为他出色的成绩和成为 独立的内科科学家。为此，已经制定了一项全面但有重点的培训方案 旨在加强莫汉达斯博士在血管生理学和分子生物学方面的培训。这包括 肾脏疾病动物模型、创新的基因组编辑工具、压力动脉造影术、 讲授细胞信号和血管生理学的课程，以及研讨会和杂志俱乐部。马克博士 西格尔是一位备受尊敬的内科医生和动脉粥样硬化和分子生物学方面的专家，他将担任 候选人的导师。已经成立了一个咨询委员会，以帮助候选人在科学和职业方面 发展包括柯克·康拉德博士(血管生理学)、彼得·萨耶斯基博士(细胞信号转导)和卡尔博士 Pepine(实验和临床心血管疾病)。 佛罗里达大学卓越的环境，丰富的临床和基础科学，以及 科学的计划和全面的培训计划，将确保莫汉达斯博士作为一名 肾脏疾病心血管并发症领域的独立研究员。