Investigating the generation of mechanical forces during tissue invagination

描述（由申请人提供）：在发育过程中，组织在称为组织形态发生的过程中被塑造成具有精确形式和功能的器官。组织形态发生由跨组织传递的细胞力引起。力的不适当产生或协调导致器官形成的缺陷，例如神经管缺陷。产生细胞力和驱动细胞形状改变的途径的异常激活可以促进癌细胞转移。因此，确定在分子、细胞和组织水平上控制组织形态发生的机制对我们理解发育和人类疾病都至关重要。 原肠胚形成和神经管闭合期间的组织内陷由上皮细胞的顶端收缩驱动。这导致柱状细胞采取楔形，这促进了上皮片的折叠。我们令人惊讶地发现，果蝇原肠胚形成过程中的顶端收缩是由脉冲收缩和随后的肌动蛋白-肌球蛋白细胞骨架的稳定化驱动的。现在已经观察到收缩脉冲促进许多不同的形态发生过程，包括组织收缩、会聚延伸和轴伸长。负责这种动态收缩的分子机制以及收缩力如何在整个组织中传递和协调尚不清楚。活体成像、定量图像分析、遗传学（突变体、RNAi）、细胞生物学（药物）、生物物理学（激光切割）和生物化学的可用性使果蝇原肠胚形成成为解决这些问题的强大系统。 我们将研究力如何从分子水平传播到组织水平。首先，我们将确定肌球蛋白运动活性和肌动蛋白丝解聚在搏动收缩过程中的作用。其次，我们将研究收缩力是如何在细胞之间传递以产生上皮张力的。第三，我们将确定生物化学和机械信号如何调节整个组织中细胞形状的协调，以及脉动是否对这种协调至关重要。 这种多学科和多尺度的方法对于了解动态分子和细胞行为如何共同导致组织形态的精确变化至关重要。我实验室的成员都有细胞生物学、遗传学、物理学和计算机科学的背景。此外，我们还与计算生物化学家和功能基因组学实验室建立了合作关系，以扩大我们的研究能力。我们准备在驱动组织形态发生的分子和细胞机制方面做出重要发现。

DESCRIPTION (provided by applicant): During development, tissues are sculpted into organs with precise forms and functions in a process called tissue morphogenesis. Tissue morphogenesis results from cellular forces that are transmitted across the tissue. Improper generation or coordination of forces leads to defects in organ formation, such as neural tube defects. Abnormal activation of pathways that generate cellular forces and drive cell shape change can promote cancer cell metastasis. Therefore, it is critical to both our understanding of development and human disease to determine the mechanisms that control tissue morphogenesis at the molecular, cellular, and tissue level. Tissue invagination during gastrulation and neural tube closure is driven by apical constriction of epithelial cells. This causes columnar cells to adopt a wedge shape, which promotes folding of the epithelial sheet. We made the surprising discovery that apical constriction during Drosophila gastrulation is driven by pulsed contractions and subsequent stabilization of the actin-myosin cytoskeleton. Contraction pulses have now been observed to promote many different morphogenetic processes, including tissue contraction, convergent extension, and axis elongation. The molecular mechanisms responsible for this dynamic contraction and how contractile force is transmitted and coordinated across the tissue is unknown. The availability of live imaging, quantitative image analysis, genetics (mutants, RNAi), cell biology (drugs), biophysics (laser cutting), and biochemistry makes Drosophila gastrulation a powerful system to address these questions. We will investigate how forces propagate from the molecular to the tissue level. First, we will determine the function of myosin motor activity and actin filament depolymerization during pulsatile contraction. Second, we will examine how contractile forces are transmitted between cells to generate epithelial tension. Third, we will determine how biochemical and mechanical signals regulate the coordination of cell shape across the tissue and whether pulsation is critical for this coordination. This multidisciplinary and multiscale approach is essential to understand how dynamic molecular and cellular behaviors collectively result in precise changes in tissue morphology. Members of my lab have backgrounds in cell biology, genetics, physics, and computer science. In addition, we have established collaborations with computational biophysicists and a functional genomics lab to expand our research capabilities. We are poised to make important discoveries regarding the molecular and cellular mechanisms that drive tissue morphogenesis.