Mechanisms Controlling Epithelial Homeostasis

描述（由申请人提供）：成人上皮组织（如皮肤、肠和肺）的持续替换和修复依赖于自我更新的干细胞，这些干细胞产生组织维持所需的特化细胞。最近的研究表明，干细胞所处的局部环境或生态位对它们的维持和功能至关重要。具体来说，干细胞在生态位中的定位使其暴露于促进其生存和维持的信号中，并指导执行正常组织功能的特化子细胞的产生。在肿瘤中发现了具有许多正常干细胞特性的自我更新细胞，这强调了在正常组织中定义干细胞控制机制对于理解干细胞如何促进癌症的重要意义。相反，利用干细胞疗法治疗与干细胞丧失相关的疾病，如糖尿病，以及对大脑、脊髓或皮肤等组织的破坏性损伤，这一想法引发了巨大的兴奋。然而，我们缺乏对干细胞在体内正常壁龛内调节机制的理解，阻碍了这些疗法在临床应用中的进展。我们提出的研究目标是了解局部信号如何促进干细胞在生态位内的规范和维持。在哺乳动物中，如小鼠或人类，主要的技术挑战使得识别组织内的成体干细胞变得困难，这一问题阻碍了识别控制干细胞行为的重要信号。正因为如此，我们将果蝇发育中的卵巢作为模型系统来直接研究上皮干细胞的调控。在识别干细胞生态位的组成部分和控制干细胞行为的特定基因方面已经取得了快速进展。重要的是，到目前为止发现的基因也调节人类干细胞，这表明发现控制果蝇干细胞功能的新信号将具有广泛的相关性。利用果蝇卵巢系统，我们最近发现整合素，一组锚定细胞的蛋白质，对于维持上皮卵泡干细胞（FSCs）在其生态位内是重要的。没有整合素，FSCs会改变形状，不正确地分裂和迁移，并失去其作为干细胞的功能。类似的缺陷被认为有助于人类癌症的发生、促进和发展。我们的数据还表明，FSCs产生的蛋白质是一个重要的生态位成分。这一新发现表明，许多类型的干细胞，可能包括癌症干细胞，可能有能力启动自己的生态位。提出的实验将定义1)整合素如何参与FSC调节和2)识别与整合素一起控制干细胞功能的重要基因和蛋白质。这些实验的结果将影响我们对上皮干细胞功能的总体理解，也将对旨在纯化干细胞用于治疗的技术的发展具有重要意义。

DESCRIPTION (provided by applicant): Continuous replacement and repair of adult epithelial tissues such as the skin, intestine, and lung depend on self-renewing stem cells which generate the specialized cells necessary for tissue maintenance. Recent work has shown that the local environment, or niche, in which stem cells reside is critical for their maintenance and function. Specifically, positioning of the stem cell within the niche exposes it to signals that promote its survival and maintenance and guide the production of specialized daughter cells that perform the normal tissue functions. Self-renewing cells that possess many normal stem cell properties have been identified in tumors, emphasizing that defining stem cell control mechanisms in normal tissues is important for understanding how stem cells contribute to cancer. Conversely, the idea of using stem cell therapeutics to treat diseases associated with stem cell loss, such as diabetes, and devastating injuries to tissues including the brain, spinal cord, or skin has generated enormous excitement. However, our lack of understanding of the mechanisms that regulate stem cells within their normal niches in vivo has hampered the advancement of these therapies for clinical applications. The goal of our proposed study is to understand how localized signals promote stem cell specification and maintenance within the niche. In mammals, like mice or humans, major technical challenges have made it difficult to identify adult stem cells within tissues, a problem that has prevented the identification of important signals that control stem cell behavior. Because of this, we are using the developing ovary in the fruit fly as a model system to directly examine epithelial stem cell regulation. Rapid progress has already been made in identifying components of the stem cell niche and specific genes that control stem cell behavior. Importantly, the genes identified so far also regulate stem cells in humans, suggesting that identifying new signals that control fly stem cell function will be broadly relevant. Using the fly ovary system, we recently found that integrins, a group of proteins that anchor cells in place, are important for maintaining epithelial Follicle Stem Cells (FSCs) within their niche. Without integrins, FSCs change shape, improperly divide and migrate, and lose their ability to function as stem cells. Similar defects are thought to contribute to cancer initiation, promotion, and progression in humans. Our data also demonstrates that FSCs produce a protein that is an important niche component. This novel finding suggests that many types of stem cells, perhaps including cancer stem cells, may have the capacity to initiate their own niche. The experiments proposed will define 1) how integrins participate in FSC regulation and 2) identify important genes and proteins that work together with integrins to control stem cell function. The outcome of these experiments will impact our understanding of epithelial stem cell function in general and also will have important implications for the development of techniques aimed at purifying stem cells for therapeutic use. PUBLIC HEALTH RELEVANCE: Our present aim is to define epithelial stem cell control mechanisms in the fly ovary, where specific stem cell regulatory genes and their functions will be determined using genetics, live imaging, and developmental techniques. Defining stem cell control mechanisms in normal tissues is important for understanding how stem cells contribute to cancer and for developing stem cell therapeutics to treat developmental defects, traumatic injury, or diseases associated with stem cell loss, including diabetes.