Polarity, growth, and morphogenesis of epithelia

上皮细胞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 架构上皮组织、生长或形态发生的缺陷是各种医学上的疾病的基础。 毁灭性的疾病，从出生缺陷到癌症。为了了解人类的生物学以及其他 在动物王国，我们需要了解上皮细胞是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中的这些问题， 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 穿越了阿尔盖尼。本MIRA应用程序中描述的研究解决了三个基本问题， 上皮生物学，范围从细胞到组织和器官尺度。 首先，上皮细胞是如何极化成互补的顶端和基底外侧区域的？我们以前的工作 将Scribble模块定义为拮抗顶端Par复合物的基底外侧调节器，但基本上 Scrib蛋白的作用、关系和效应伴侣的问题仍然没有答案， 将极性调节剂与核心细胞运输机制联系起来的分子机制。第二， 上皮组织中的生长控制与细胞极性的耦合机制？我们和其他人已经证明了这种极性 通过遗传或物理手段的破坏激活了促有丝分裂信号，这表明上皮完整性是一个重要因素。 用于保持适当尺寸并确保维修的内在控制系统。但上皮细胞的破裂 体内平衡被检测到触发增殖是不理解的。第三，如何3D，多组分器官 获得它们独特的形状当前强调细胞自主性肌球蛋白II收缩性的范例源自 分析二维细胞层的结果通过研究一个简单的3D管状器官，我们发现了多个新的 包括一种新的形态发生运动和一种不受重视的器官成形机制的现象 涉及细胞外基质硬度。在理解细胞和细胞外力量如何 被整合以驱动特定的细胞行为;我们的专业知识使我们能够缩小这些差距， 全面了解器官形态发生。 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 与先进的成像新工具，与物理科学家的合作，以及新的 实验系统我们的研究结果将增强我们对保守机制的理解， 功能性上皮器官在发育过程中，并可能提供新的见解上皮起源的疾病。

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.