Polarity, growth, and morphogenesis of epithelia

上皮是动物的核心细胞类型，构成了最广泛和最古老的组织模式 建筑。上皮组织、生长或形态发生的缺陷是多种医学疾病的基础 破坏性的疾病，从出生缺陷到癌症。了解人类的生物学以及人类的其他生物 动物王国，我们需要了解上皮细胞如何呈现其独特的形式，以及这种形式如何使 功能。我的实验室使用一套独特的多学科策略来研究果蝇的这些问题， 利用上皮生物学的深层进化保守性来揭示适用的一般原则 在整个系统发展史上。此Mira应用程序中描述的研究解决了以下三个基本问题 上皮生物学，从细胞到组织和器官的尺度。 首先，上皮细胞是如何极化成互补的顶区和基底侧区的？我们之前的工作 将Scribble模块定义为对抗心尖PAR复合体的基侧调节因子，但基本 关于Scrib蛋白的作用、关系和效应伙伴的问题仍然没有答案，就像 将极性调节器与核心细胞运输机制联系起来的分子机制。第二，什么 上皮组织的生长控制与细胞的极性有关的机制？我们和其他人已经证明了两极 通过遗传或物理手段的破坏激活了有丝分裂信号，这表明上皮完整性是一种 内部控制系统，用于保持适当的尺寸和确保维修。但上皮细胞的破损是如何 检测到动态平衡是否会引发细胞增殖尚不清楚。第三，3D、多成分器官是如何 获得了它们独特的形状？当前强调细胞自主肌球蛋白II收缩能力的范式源于 从分析二维单元格图纸开始。通过研究一个简单的3D管状器官，我们发现了多部小说 包括一种新的形态发生运动和一种未知的器官塑造机制 涉及细胞外基质僵硬。在理解细胞和细胞外力如何 被集成到一起来驱动特定的细胞行为；我们的专业知识使我们能够弥合这些差距，并 探讨对器官形态发生的全面理解。 拟议中的实验通过结合果蝇遗传学的传统优势来解决这些问题 通过先进成像的新工具，与物理学家的合作，以及新技术的开发 实验系统。我们的结果将增强我们对产生 在发育过程中的功能性上皮器官，并可能为上皮源性疾病提供新的见解。

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.