CAREER:Engineering Functional Tissue Assembly and Remodeling Through Developmental Biology

在胚胎发生期间，组织组装和重塑的速度明显快于成年期，但这些机制尚不清楚。有效的策略来控制组织适应和重塑，以及加速心血管组织替代物的建设，可以利用“自然工程”范式，规定心血管的发展和成熟。这一建议将揭示这些机制的心脏瓣膜，一个至关重要的心血管软组织。指导假设是，心脏瓣膜组织组装和重塑是由一个机械敏感的遗传信号网络控制的，该信号网络在瓣膜形成期间活跃，在老化瓣膜中重新激活。这一建议解决了我们对组织组装和重塑过程的理解的根本差距，具有独特的实验和计算工具。这些研究将首次提供整合器官、组织、细胞和分子长度尺度的机制见解，这将改变工程策略，以控制生命周期任何阶段的瓣膜重塑。一个新的活胚胎培养系统的实施将加强研究性学习课程。在研究生阶段，发育生物学和工程学的融合将为专业学生提供所需的广度。适合小鼠组织的独特实验工具将使亚致死基因突变重要功能后果的定量机制理解成为可能。本方案中实现的可见活胚胎系统可以作为向公众和科学界传达许多基本现象的中心。这将增强人们对科学进步的认识和赞赏。

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.