Polarity, growth, and morphogenesis of epithelia

上皮细胞的极性、生长和形态发生

基本信息

批准号：
10548124
负责人：
David Bilder
金额：
$ 81.97万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2024-02-29
项目状态：
已结题

项目摘要

Epithelia are the core cell type of animals, and constitute the most widespread and ancient mode of tissue architecture. Defects in epithelial organization, growth, or morphogenesis underlie a variety of medically devastating disorders, from birth defects to cancer. To understand the biology of humans as well as the rest of the animal kingdom, we need to understand how epithelia take on their distinctive form and how this form enables function. My lab uses a distinctive set of multidisciplinary strategies to investigate these questions in Drosophila, leveraging the deep evolutionary conservation of epithelial biology to uncover general principles applicable across phylogeny. The research described in this MIRA application tackles three fundamental problems of epithelial biology, ranging from the cellular to the tissue and organ scales. First, how are epithelial cells polarized into complementary apical and basolateral domains? Our previous work defined the Scribble module as a basolateral regulator that antagonizes the apical Par complex, but basic questions of the role, relationship, and effector partners of the Scrib proteins remain unanswered, as are the molecular mechanisms that link polarity regulators to the core cellular trafficking machinery. Second, what mechanisms couple growth control in epithelial tissues to cell polarity? We and others have shown that polarity disruption by genetic or physical means activates mitogenic signaling, suggesting that epithelial integrity is an intrinsic control system used to maintain proper size and ensure repair. But how breaches in epithelial homeostasis are detected to trigger proliferation is not understood. Third, how do 3D, multicomponent organs acquire their distinctive shapes? Current paradigms emphasizing cell-autonomous Myosin II contractility derive from analyzing 2D cellular sheets. By studying a simple 3D tube-like organ, we have uncovered multiple novel phenomena including a new morphogenetic movement and an unappreciated mechanism for organ shaping involving extracellular matrix stiffness. Major gaps exist in understanding how cellular and extracellular forces are integrated to drive specific cell behaviors; our expertise uniquely positions us to close these gaps and approach an in toto understanding of organ morphogenesis. The proposed experiments tackle these questions by combining the traditional strengths of Drosophila genetics with new tools with advanced imaging, collaborations with physical scientists, and the development of novel experimental systems. Our results will enhance our understanding of the conserved mechanisms that generate functional epithelial organs during development, and may provide new insights into diseases of epithelial origin.

上皮是动物的核心细胞类型，构成最广泛，最古老的组织模式建筑学。上皮组织，生长或形态发生的缺陷是多种医学上的基础从出生缺陷到癌症的毁灭性疾病。了解人类的生物学以及其余的动物王国，我们需要了解上皮在其独特的形式以及这种形式如何启用的方式功能。我的实验室使用一组独特的多学科策略来研究果蝇中的这些问题，利用上皮生物学的深度进化保护揭示适用的一般原则跨系统发育。 MIRA应用中描述的研究解决了三个基本问题上皮生物学，从细胞到组织和器官尺度。首先，上皮细胞如何极化为互补的顶端和基底外侧结构域？我们以前的工作将涂鸦模块定义为拮抗顶端par复合物但基本的基底外侧调节器 SCRIB蛋白的角色，关系和效应伙伴的问题仍然没有得到解答，将极性调节因子与核心细胞运输机制联系起来的分子机制。第二，什么机制将上皮组织中的生长控制与细胞极性？我们和其他人表明了极性通过遗传或物理手段破坏会激活有丝分裂信号传导，表明上皮完整性是一种用于维持适当尺寸并确保维修的内在控制系统。但是如何在上皮中违反检测到稳态以触发增生。第三，如何3D，多组件器官获得独特的形状？当前强调细胞自主肌球蛋白II收缩力得出的范式通过分析2D细胞片。通过研究简单的3D管状器官，我们发现了多个小说现象包括新的形态发生运动和器官塑形的未欣赏机制涉及细胞外基质刚度。理解细胞和细胞外力的主要差距集成以驱动特定的细胞行为；我们的专业知识独特地定位了我们缩小这些差距，并接近对器官形态发生的理解。提出的实验通过结合果蝇遗传学的传统优势来解决这些问题借助具有高级成像的新工具，与物理科学家的合作以及新颖的新工具实验系统。我们的结果将增强我们对产生的保守机制的理解开发过程中功能性上皮器官，并可能为上皮起源疾病提供新的见解。