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?

心血管疾病是慢性肾脏病（CKD）的主要死亡原因。动脉硬化是 CKD增加，与死亡率相关，被认为是心血管不良反应的关键介质。 事件然而，CKD导致动脉硬化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。 我们的新的初步数据表明赖氨酰氧化酶（LOX），一种交联胶原蛋白的酶， 弹性蛋白在CKD的血管平滑肌细胞中上调，可能有助于增加动脉粥样硬化。 刚度增加的硬度反过来激活rho激酶亚型ROCK 1，ROCK 1已被证明是 增加血管平滑肌细胞迁移和增殖。这些数据表明动脉粥样硬化 可能是僵硬的结果，并指出CKD中的原发性血管平滑肌细胞功能障碍。 该建议的具体目的是（1）表征赖氨酰氧化酶在介导动脉僵硬中的作用 在CKD中，（2）确定ROCK 1在调节CKD中平滑肌迁移和增殖中的作用， 对僵硬的反应，和（3）评估赖氨酰氧化酶和rho激酶在CKD动脉粥样硬化中的作用 体内模型。这些具体目标的成功完成将确定目标船只的潜力 僵硬作为一个潜在的机制，以防止CKD的血管功能障碍。血管平滑肌细胞 可能成为CKD患者心血管并发症预防的新靶点， 为莫汉达斯博士开发一条独立的研究路线 博士Mohandas完成了NIH赞助的T32研究奖学金，发表了13篇第一或资深作者的论文。 论文，并在国家和国际科学会议上发表。他被聘为“终身教职人员 佛罗里达大学的助理教授，因为他出色的业绩记录和潜力， 独立的医学科学家。为此，一项全面但有重点的培训方案已在 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训练。这包括 肾脏疾病动物模型的实践培训，创新的基因组编辑工具，压力动脉造影， 细胞信号和血管生理学的教学课程，以及研讨会和期刊俱乐部。马克博士 西格尔是一位德高望重的医生，也是动脉粥样硬化和分子生物学方面的专家， 候选人的导师一个咨询委员会已经成立，以帮助候选人在科学和职业生涯 包括Kirk Conrad博士（血管生理学），Peter Sayeski博士（细胞信号传导）和Carl博士 Pepine（实验和临床心血管疾病）。 佛罗里达大学的杰出环境，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成功地作为一个 肾脏疾病心血管并发症领域的独立研究者。

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.