Mechanisms Controlling Epithelial Homeostasis

控制上皮稳态的机制

基本信息

批准号：
8142785
负责人：
Alana M O'Reilly
金额：
$ 33.17万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
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/8142785
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 Public Health 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

项目摘要

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.

描述（由申请人提供）：皮肤、肠和肺等成体上皮组织的持续更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专门细胞。最近的研究表明，干细胞所在的局部环境或生态位对其维持和功能至关重要。具体来说，干细胞在微环境中的定位使其暴露于促进其生存和维持的信号，并指导执行正常组织功能的专门子细胞的产生。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，这强调了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非常重要。相反，使用干细胞疗法来治疗与干细胞损失相关的疾病（例如糖尿病）以及对大脑、脊髓或皮肤等组织的破坏性损伤的想法引起了极大的兴奋。然而，我们对体内正常生态位内调节干细胞的机制缺乏了解，阻碍了这些疗法在临床应用中的进展。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。在小鼠或人类等哺乳动物中，重大的技术挑战使得识别组织内的成体干细胞变得困难，这一问题阻碍了控制干细胞行为的重要信号的识别。因此，我们使用果蝇发育中的卵巢作为模型系统来直接检查上皮干细胞的调节。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，迄今为止发现的基因也调节人类干细胞，这表明识别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（一组将细胞锚定在适当位置的蛋白质）对于维持上皮卵泡干细胞（FSC）在其生态位内非常重要。如果没有整合素，FSC 会改变形状、不正确地分裂和迁移，并失去作为干细胞发挥作用的能力。类似的缺陷被认为会导致人类癌症的发生、发展和进展。我们的数据还表明，FSC 产生的蛋白质是重要的利基成分。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，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用途的技术的发展产生重要影响。公共健康相关性：我们目前的目标是定义果蝇卵巢中的上皮干细胞控制机制，其中特定的干细胞调节基因及其功能将使用遗传学、实时成像和发育技术来确定。定义正常组织中的干细胞控制机制对于了解干细胞如何导致癌症以及开发干细胞疗法来治疗发育缺陷、创伤性损伤或与干细胞丢失相关的疾病（包括糖尿病）非常重要。