Investigating the generation of mechanical forces during tissue invagination

研究组织内陷过程中机械力的产生

• 批准号: 9260898
• 负责人: Adam Christopher Martin
• 金额: $ 29.08万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260898
• 关键词: Ablation; Actins; Address; Adherens Junction; Adopted; Alpha Cell; Apical; Behavior; Biochemical; Biochemistry; Biophysics; Cell Adhesion; Cell Culture Techniques; Cell Shape; Cell-Cell Adhesion; Cells; Cellular biology; Collaborations; Columnar Cell; Congenital Abnormality; Cytoskeletal Proteins; Cytoskeleton; Data; Defect; Development; Drosophila genus; Embryonic Development; Epithelial; Epithelial Cells; Exhibits; F-Actin; G Protein-Coupled Receptor Signaling; GTP-Binding Protein alpha Subunits, Gs; Generations; Genetic; Image; Image Analysis; In Vitro; Individual; Lasers; Life; Mechanics; Microfilaments; Molecular; Morphogenesis; Morphology; Motor; Motor Activity; Movement; Myosin ATPase; Myosin Type II; Nature; Neoplasm Metastasis; Neural Tube Closure; Neural Tube Defects; Organ; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physics; Physiologic pulse; Population; Process; Proteins; RNA Interference; Research; Role; Shapes; Signal Pathway; Signal Transduction; Spinal Dysraphism; System; Tissues; Work; cancer cell; cell behavior; cell motility; computer science; constriction; convergent extension; crosslink; defined contribution; depolymerization; functional genomics; gastrulation; human disease; in vivo; insight; interdisciplinary approach; mechanical force; member; multidisciplinary; mutant; public health relevance; quantitative imaging; transmission process; tumor progression

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.

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雕刻成具有精确形式和功能的器官。组织形态发生是由跨组织传递的细胞力产生的。力的不当产生或协调会导致器官形成缺陷，例如神经管缺陷。产生细胞力和驱动细胞形状变化的通路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于我们理解发育和人类疾病至关重要。 原肠胚形成和神经管闭合过程中的组织内陷是由上皮细胞的顶端收缩驱动的。这导致柱状细胞呈楔形，促进上皮片的折叠。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肌动蛋白-肌球蛋白细胞骨架的脉冲收缩和随后的稳定驱动的。现在已观察到收缩脉冲可促进许多不同的形态发生过程，包括组织收缩、会聚伸展和轴伸长。造成这种动态收缩的分子机制以及收缩力如何在组织中传递和协调尚不清楚。实时成像、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得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，我们将确定脉动收缩期间肌球蛋白运动活动和肌动蛋白丝解聚的功能。其次，我们将研究收缩力如何在细胞之间传递以产生上皮张力。第三，我们将确定生化和机械信号如何调节组织内细胞形状的协调，以及脉动是否对于这种协调至关重要。 这种多学科和多尺度的方法对于理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。我实验室的成员拥有细胞生物学、遗传学、物理学和计算机科学背景。此外，我们还与计算生物物理学家和功能基因组学实验室建立了合作，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取得重要发现。