Mechanisms Controlling Epithelial Homeostasis

控制上皮稳态的机制

• 批准号: 8509528
• 负责人: Alana M O'Reilly
• 金额: $ 31.48万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-14 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509528
• 关键词: Adhesions; Adhesives; Adult; Affect; Basement membrane; Behavior; Biological Models; Brain; Cell Cycle; Cell Proliferation; Cell Shape; Cell division; Cell physiology; Cells; Characteristics; Competitive Behavior; Data; Defect; Development; Diabetes Mellitus; Disease; Drosophila genus; Employee Strikes; Environment; Epithelial; Epithelium; Erinaceidae; Event; Extracellular Matrix; Female; Gene Proteins; Generations; Genes; Genetic; Goals; Homeostasis; Human; Image; Injury; Integrins; Intestines; Lead; Life; Ligands; Longevity; Lung; Maintenance; Malignant Neoplasms; Mammals; Mediating; Mitotic spindle; Modeling; Molecular Genetics; Morphology; Multipotent Stem Cells; Mus; Mutation; Normal tissue morphology; Outcome; Ovarian; Ovary; Pathway interactions; Positioning Attribute; Process; Production; Property; Proteins; Regulation; Regulator Genes; Research; Role; Shapes; Signal Transduction; Skin; Specific qualifier value; Spinal Cord; Stem cells; System; Systems Analysis; Techniques; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Work; adult stem cell; cancer initiation; cancer stem cell; cell behavior; cellular imaging; clinical application; daughter cell; fly; in vivo; mutant; novel; precursor cell; prevent; public health relevance; repaired; research study; self renewing cell; self-renewal; smoothened signaling pathway; stem cell division; stem cell fate specification; stem cell niche; technique development; tumor

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.

描述（由申请人提供）：连续更换和修复成年上皮组织，例如皮肤，肠和肺部，取决于自我更新的干细胞，这些干细胞产生了组织维持所需的专业细胞。最近的工作表明，干细胞居住的局部环境或利基市场对于其维护和功能至关重要。具体而言，将干细胞的定位在利基市场中暴露于促进其存活和维持的信号，并指导执行正常组织功能的专用子细胞的产生。在肿瘤中已经鉴定出具有许多正常干细胞特性的自我更新细胞，这强调定义正常组织中的干细胞控制机制对于理解干细胞如何促进癌症很重要。相反，使用干细胞疗法来治疗与干细胞损失有关的疾病，例如糖尿病，以及对包括大脑，脊髓或皮肤在内的组织的破坏性损伤引起了巨大的兴奋。但是，我们缺乏对体内正常壁细胞中干细胞的机制的了解，阻碍了这些疗法用于临床应用的进步。 我们拟议的研究的目的是了解局部信号如何促进利基内的干细胞规范和维护。在小鼠或人类等哺乳动物中，主要的技术挑战使得难以识别组织中的成年干细胞，这一问题阻止了鉴定控制干细胞行为的重要信号。因此，我们将果蝇中发育中的卵巢用作模型系统直接检查上皮干细胞调节。在识别控制干细胞行为的特定基因的成分方面已经取得了快速的进步。重要的是，到目前为止鉴定出的基因还调节了人类中的干细胞，这表明鉴定控制蝇干细胞功能的新信号将广泛相关。 使用卵巢系统，我们最近发现，整联蛋白是一组锚定细胞的蛋白质，对于将上皮卵泡干细胞（FSC）保持在其利基市场中很重要。没有整合素，FSC会改变形状，不适当地分裂和迁移，并失去其充当干细胞的能力。人们认为类似的缺陷会导致人类的癌症开始，促进和进展。我们的数据还表明，FSC会产生一种重要的利基成分蛋白质。这一新颖的发现表明，许多类型的干细胞（可能包括癌症干细胞）可能具有启动自己的利基市场的能力。提出的实验将定义1）整联蛋白如何参与FSC调节，2）确定与整合素一起使用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理解，并且对旨在净化干细胞治疗用途的技术的发展具有重要意义。