CAREER: Biophysical Mechanisms Underlying the Generation of Tissue Structure and Mechanics

该学院早期职业发展计划(CALEAR)研究将开发与活组织结构和力学相关的新知识，并将通过有针对性的教育活动培训工程师参与生物工程。基因的活动直接指导组织和器官的形成，但组织的适当形状、结构和机械性能也受到发育过程中内部和外部负荷的指导。众所周知，异常的组织属性会伴随着出生缺陷和癌症一起发生，但这些异常是遗传的还是由异常的机械负荷引起的，目前还不清楚。机械因素和遗传因素是如何共同作用形成正常组织的，目前还知之甚少。这项研究将通过分离组织发育中的遗传和机械效应，改善对出生缺陷和癌症的根本原因的理解。这项工作是朝着开发预防或治疗这些疾病的疗法迈出的重要一步。控制基因表达和内部细胞负载的新工具也可能使组织工程和再生医学的新战略成为可能，为科学进步和促进国民健康做出贡献。教育目标是让来自不同背景的学生参与研究。IHE的研究将被整合到：(1)通过哥伦比亚工程学ENG计划为未被充分代表的少数族裔高中生提供机会；(2)通过哥伦比亚工程学暑期计划为本科生女性提供职业发展和暑期研究指导；以及(3)一门关于形态发生：生物材料中的形状和结构的新课程，旨在引导高水平的本科生和研究生工程学学生研究力学和生物学之间的界面。该项目将研究几个与组织和器官的构建有关的基于力学的问题，特别是如何通过基于钙粘素的细胞-细胞接触来传递肌动蛋白的张力，以调节上皮组织的形态发生。计划了三个目标，包括：(1)测试组织结构是如何受力控制的，(2)确定驱动细胞形状变化的细胞重排，以及(3)研究这些变化如何影响组织力学。这项研究将促进对机械因素如何与生物因素结合来构建和塑造活组织的基本理解，填补我们对机械在发育过程中将基因型转换为表型所起作用的理解方面的空白。这项研究将利用模式生物黑腹果蝇，将生物力学和共聚焦成像研究与细胞力产生和力学的系统光遗传学操作相结合，以确定在胚胎发育期间，由E-钙粘附素介导的细胞肌球蛋白收缩和黏附产生的张力如何控制上皮组织的形状、结构和力学。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development Program (CAREER) research will develop new knowledge related to the structure and mechanics of living tissues and will train engineers to participate in bioengineering using targeted educational activities. The activities of genes direct the formation of tissues and organs but the proper shape, structure, and mechanical properties of the tissues are also guided by internal and external loading during development. It is known that abnormal tissue properties occur along with birth defects and cancer, but the extent that the abnormalities are genetic or occur from aberrant mechanical loads isn't known. It remains poorly understood how the mechanical and genetic factors work together to build normal tissues. The research will build an improved understanding of the underlying causes of birth defects and cancer by separating genetic from mechanical effects in tissue development. The work is an essential step toward the development of therapies to prevent or treat these diseases. The novel tools to control genetic expression and internal cell loading may also enable new strategies for tissue engineering and regenerative medicine, contributing to the progress of science and to the advancement of national health. The educational goal is to engage students from a variety of backgrounds in research. Ihe research will be integrated into: (1)opportunities for underrepresented minority high school students through the Columbia Engineering E.N.G. program; (2) career development and summer research mentoring for undergraduate women through the Columbia Engineering Summer@SEAS Program; and (3)a new course on Morphogenesis: shape and structure in biological materials aimed at introducing upper level undergraduate and graduate engineering students to research at the interface between mechanics and biology.The project will study several mechanics-based questions about the construction of tissues and organs, specifically how actomyosin-based tension is transduced through cadherin-based cell-cell contacts to regulate epithelial tissue morphogenesis. Three objectives are planned and include: (1) testing how tissue structure is controlled by forces, (2) determining the cellular rearrangements that drive cell shape changes, and (3) studying how these changes affect tissue mechanics. The research will advance fundamental understanding of how mechanical factors couple with biological factors to build and shape living tissues, filling a gap in our understanding of the role that mechanics plays in translating genotype to phenotype during development. The research will utilize the model organism Drosophila melanogaster and combine biomechanical and confocal imaging studies with systematic optogenetic manipulation of cellular force generation and mechanics in order to determine how tension generated by cellular actomyosin contractility and adhesion mediated by E-cadherin at cell-cell contacts control epithelial tissue shape, structure, and mechanics during embryonic development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.