Mechanobiology of Endothelial-to-Mesenchymal Transition in Cardiovascular Calcification

心血管钙化中内皮向间质转化的力学生物学

• 批准号: 10625842
• 负责人: Jeffrey John Hsu
• 金额: $ 11.84万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625842
• 关键词: Acceleration; Adult; Aorta; Apolipoprotein E; Arterial Fatty Streak; Attenuated; Balloon Angioplasty; Blood Vessels; Calcium; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell Line; Cells; Cerebral Infarction; Complex; Congestive Heart Failure; Cytoskeleton; Deposition; Detection; Development; Disease; Embryo; Endothelial Cells; Endothelium; Event; Foundations; Gene Expression; Genetic; Goals; Heart; Heart Valves; Histologic; Individual; Inflammatory; Investigation; K-Series Research Career Programs; Mechanics; Mediating; Medical; Mentors; Mentorship; Mesenchymal; Methods; Minerals; Morbidity - disease rate; Morphology; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nature; Osteogenesis; PTH gene; Pathologic; Pathologic Processes; Physiological Processes; Population; Predisposition; Process; Property; Public Health; Research; Research Personnel; Resolution; Resources; Risk; Rupture; Signal Transduction; Sodium Fluoride; Speed; Stress; TNF gene; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Training; Translational Research; Vascular calcification; Work; X-Ray Computed Tomography; biomechanical test; biomineralization; bone; calcification; cardiovascular health; career; career development; cytokine; efficacy evaluation; experimental study; improved; in vivo; innovation; insight; interstitial; mechanical properties; migration; mortality; mouse model; novel; osteogenic; personalized medicine; physician-scientist training program; pressure; protein expression; sex; targeted agent; targeted treatment; therapeutic evaluation; therapeutic target; transcription factor; western diet

ABSTRACT This proposal describes a five-year mentored physician-scientist training program to characterize the mechanobiology of endothelial-to-mesenchymal transition (EndMT) in cardiovascular calcification. Cardiovascular calcification is a highly prevalent process whereby calcium mineral forms within the blood vessels and heart tissue, and its presence is associated with an increased risk of morbidity and mortality. Despite decades of research, there remains no effective medical therapy to treat this process. Recent work has implicated EndMT in cardiovascular calcification. EndMT describes the phenomenon whereby endothelial cells lining the lumen of the heart valves or blood vessels are stimulated to dedifferentiate into mesenchymal cells. Subsequently, these mesenchymal cells are capable of differentiating into various lineages, including the chondrogenic and osteogenic lineages that can promote calcification. While EndMT is a promising target for therapeutic intervention in cardiovascular calcification, characterizing the EndMT process in experimental studies can be challenging. Current methods to assess EndMT, such as genetic lineage tracing studies and immunostaining detection of endothelial and mesenchymal marker expression, are labor-, resource-, and time- intensive. Further, these methods are binary assessments of EndMT and do not capture an important aspect of the process – its dynamic mechanical nature. Endothelial cells undergoing EndMT alter their cytoskeletal mechanics, detach from their neighboring cells, and migrate into the interstitial space. Thus, their mechanical properties, or “mechanophenotype,” during EndMT are likely dynamic, but have not been previously explored. In this proposal, we outline our aims to characterize the mechanophenotypes of EndMT, with the hope of developing novel, high-throughput platforms to more rapidly identify possible therapeutic targets for EndMT- related disease, including cardiovascular calcification. Further, the accompanying mentored career development training plan will allow the candidate to develop the expertise needed to successfully complete this project and will provide him with the mentorship and support necessary to become a fully independent scientific investigator. In line with the strategic goals of the NHLBI, the aims of this proposal focus on: (1) elucidating our understanding of the pathobiology of EndMT and cardiovascular calcification, and (2) developing innovative new platforms to accelerate our ability to identify therapeutic targets for these processes, thereby advancing translational research.

抽象的 该建议描述了一个五年的身体科学训练计划，以表征 心血管钙化中内皮到间质转变（ENDMT）的机械生物学。 心血管钙化是一个高度普遍的过程，在血管中钙矿物质形成 和心脏组织及其存在与发病率和死亡率的增加有关。尽管 数十年的研究，仍未有效治疗这一过程。最近的工作有 在心血管钙化中实施的EndMT。 EndMT描述了内皮细胞的现象 刺激心脏瓣膜或血管的腔内衬里，以将其推导到间充质细胞中。 随后，这些间充质细胞能够分化为各种谱系，包括 可以促进钙化的软骨发育和成骨谱系。而EndMt是一个承诺的目标 心血管钙化中的治疗干预，表征实验中的ENDMT过程 研究可能会受到挑战。当前评估EndMT的方法，例如遗传谱系追踪研究和 内皮和间质标记表达的免疫染色检测是劳动，资源和时间 - 密集的。此外，这些方法是对EndMT的二进制评估，并且不会捕获 该过程 - 它的动态机械性质。内皮细胞正在发生终极细胞改变其细胞骨架 力学，脱离其相邻细胞，并迁移到间质空间中。那是他们的机械 在EndMT期间的性质或“机械表型”可能是动态的，但以前尚未探索。 在此提案中，我们概述了表征EndMT机械型的目标，希望 开发新型的高通量平台，以更快地确定Endmt-的可能的治疗靶标 相关疾病，包括心血管计算。此外，参与的职业发展 培训计划将使候选人能够开发成功完成该项目所需的专业知识，并且 将为他提供成为完全独立的科学研究者所必需的精神和支持。 符合NHLBI的战略目标，该提案的目的重点是：（1）阐明我们的理解 EndMT和心血管钙化的病理生物学，以及（2）开发创新的新平台 加速我们识别这些过程的治疗靶标的能力，从而推进翻译 研究。