CAREER:Engineering Functional Tissue Assembly and Remodeling Through Developmental Biology

在胚胎发育过程中，组织组装和重塑的速度明显快于成年期，但人们对这些机制知之甚少。控制组织适应和重塑以及加速构建心血管组织替代物的有效策略，可以通过利用规定心血管发育和成熟的“自然工程”范例来获得。这项提案将揭示心脏瓣膜的这些机制，心脏瓣膜是一种至关重要的心血管软组织。指导性假设是心脏瓣膜组织的组装和重塑是由机械敏感的遗传信号网络控制的，该网络在瓣膜形成过程中活跃，在老化的瓣膜中重新激活。这一建议通过独特的实验和计算工具解决了我们对组织组装和重塑过程的理解上的一个根本空白。这些研究将提供第一个将器官、组织、细胞和分子长度尺度结合在一起的机械性见解，这些尺度将改变工程策略，以控制生命周期中任何阶段的瓣膜重塑。新的活体胚胎培养系统的实施将加强探究式学习课程。在研究生水平上吸收发育生物学和工程学将给专业学生提供急需的广度。适用于小鼠组织的独特实验工具将使人们能够从定量的机制上理解亚致死基因突变的重要功能后果。这项提案中实施的可见活胚胎系统可以作为中心，向普通公众以及科学界传达许多基本现象。这将提高人们对科学进步的认识和欣赏。

Tissue assembly and remodeling occurs at significantly faster rates during embryogenesis than in adulthood, but these mechanisms are poorly understood. Efficient strategies to control tissue adaptation and remodeling, as well as accelerate the construction of cardiovascular tissue replacements, can be gained by harnessing "natural engineering" paradigms that prescribe cardiovascular development and maturation. This proposal will uncover these mechanisms for heart valves, a critically important cardiovascular soft tissue. The guiding hypothesis is that heart valve tissue assembly and remodeling is controlled by a mechanically sensitive genetic signaling network that is active during valvulogenesis and reactivated in aged valves.This proposal addresses a fundamental gap in our understanding of tissue assembly and remodeling processes with unique experimental and computational tools. These studies will provide first mechanistic insights integrating organ, tissue, cell, and molecular length scales that will transform engineering strategies to control valvular remodeling at any stage in the lifecycle. Implementation of a novel living embryo culture system will enhance inquiry based learning curricula. Assimilation of developmental biology and engineering at the graduate level will give specialized students much needed breadth. Unique experimental tools suitable for mouse tissues will enable quantitative mechanistic understanding of important functional consequences of sublethal genetic mutations. The visible living embryo system implemented in this proposal can be used as a centerpiece to communicate many basic phenomena to the general public as well as the scientific community. This will augment awareness and appreciation for the advancement of science.