Mechanisms Controlling Epithelial Homeostasis

描述(申请人提供)：成人上皮组织，如皮肤、肠道和肺的持续替换和修复依赖于自我更新的干细胞，它产生组织维持所需的特化细胞。最近的研究表明，干细胞所在的当地环境或利基环境对它们的维护和功能至关重要。具体地说，干细胞在利基内的定位使其暴露在促进其生存和维持的信号中，并指导产生执行正常组织功能的特化子代细胞。具有许多正常干细胞特性的自我更新细胞已经在肿瘤中被发现，强调在正常组织中确定干细胞控制机制对于理解干细胞如何促进癌症非常重要。相反，使用干细胞疗法来治疗与干细胞丢失相关的疾病，如糖尿病，以及对大脑、脊髓或皮肤等组织的毁灭性损伤，这一想法引起了极大的兴奋。然而，我们对干细胞在体内正常环境中的调节机制缺乏了解，阻碍了这些疗法在临床应用中的进步。我们提出的研究的目标是了解局部信号如何促进干细胞在利基内的规范和维持。在哺乳动物中，如老鼠或人类，重大的技术挑战使识别组织中的成年干细胞变得困难，这一问题阻碍了控制干细胞行为的重要信号的识别。正因为如此，我们正在使用果蝇发育中的卵巢作为一个模型系统来直接检测上皮干细胞的调节。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的干细胞，这表明识别控制苍蝇干细胞功能的新信号将具有广泛的相关性。利用苍蝇卵巢系统，我们最近发现整合素，一组将细胞固定在适当位置的蛋白质，对于维持上皮毛囊干细胞(FSCS)在其利基内是重要的。如果没有整合素，干细胞就会改变形状，不正确地分裂和迁移，失去作为干细胞的功能。类似的缺陷被认为是人类癌症的启动、促进和进展的原因。我们的数据还表明，FSCs产生一种蛋白质，这是一个重要的利基成分。这一新的发现表明，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利基。拟议的实验将定义1)整合素如何参与FSC调节，2)识别与整合素一起工作以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影响。

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.