CAREER: Understanding Endothelial-Mesenchymal Transformation in the Heart Valve

该NSF教师早期职业发展（CAREER）计划奖将研究心脏瓣膜细胞通过称为内皮-间充质转化（EndoMT）的过程从稳定的内皮状态转变为移动的间充质状态的机制。心脏瓣膜是复杂的结构，在复杂的机械环境中发挥作用，在正常人的一生中通过打开和关闭超过30亿次来引导流动。该瓣膜在循环系统中是独一无二的，因为它能够进行EndoMT，这是一个对胚胎生长至关重要的过程，也是瓣膜如何适应机械环境以维持自身并对损伤做出反应的过程。该奖项将支持EndoMT机械生物学的基础研究，以确定血液的摩擦，瓣膜的弯曲和其他机械效应如何改变活组织的生物反应。更广泛的影响包括开发新的瓣膜疾病治疗方法和改进组织工程策略以构建新的心脏瓣膜。教育部分的重点是在为期一周的夏令营中让代表性不足的高中毕业生接触多学科工程研究。该夏令营将整合机械生物学和人工组织制造的理论和实践，并计划提高学生对科学和工程的认识和兴趣。该奖项的研究目标是促进对细胞结构，建筑和机械环境在EndoMT调控中的作用的理解。为了理解这种现象，将进行以下目标：（I）设计将限定的应变、流体流动和基底刚度应用于瓣膜内皮细胞的微制造系统。(II)在模拟早期发育、稳态、生长、损伤和疾病的机械和结构机制下，使用实时成像检查这些细胞中的EndoMT过程。(III)检查通过药理学抑制或基因缺失控制EndoMT过程的机械调节基因。该奖项将为心脏瓣膜细胞表型和可塑性的机械调节以及控制这些过程的关键信号分子提供重要见解。

This NSF Faculty Early Career Development (CAREER) Program award will study the mechanisms by which the cells of the heart valve can change from a stable, endothelial state into a mobile, mesenchymal state, via a process termed endothelial-mesenchymal transformation (EndoMT). Heart valves are sophisticated structures that function in a complex mechanical environment, directing flow by opening and closing more than three billion times during a normal human lifetime. The valve is unique within the circulatory system in its ability to undergo EndoMT, a process that is crucial to the growing embryo, and also to how the valve adapts to the mechanical environment to maintain itself and to respond to injury. The award will support fundamental research into the mechanobiology of EndoMT to determine how friction of the blood, flexing of the valve and other mechanical effects change the biological response of the living tissue. Broader impacts include the development of new treatments for valve disease and improving tissue engineering strategies to build new heart valves. The educational component is centered on exposing underrepresented high-school seniors to multidisciplinary engineering research at a week-long summer camp. The camp will integrate theory and practice of mechanobiology and artificial tissue fabrication, and is planned to increase student awareness and interest in science and engineering.The research objective of this award is to advance the understanding of the role of cellular structure, architecture and mechanical milieu in the regulation of EndoMT. The following objectives are to be undertaken to understand this phenomenon: (I) Engineer a microfabricated system that applies defined strain, fluid flow and substrate stiffnesses to valve endothelial cells. (II) Examine the EndoMT process in these cells under mechanical and architectural regimes that mimic early development, homeostasis, growth, injury and disease using live imaging. (III) Examine the mechanoregulatory genes that control the EndoMT process via pharmacological inhibition or gene deletion. This award will provide important insights into the mechanoregulation of cellular phenotype and plasticity in the cardiac valve, and the key signaling molecules that control these processes.