Characterization of intestinal stem cells (research project)

描述（由申请人提供）：存在于相互作用的小生境中的肠干细胞已被广泛接受为肠上皮持续自我更新的来源。然而，虽然其他器官系统已经认识到在鉴定干细胞群体和利用该知识用于疾病的治疗性治疗方面的实质性进展，但是肠干细胞领域的进展由于不能明确地鉴定、分离和生长干细胞群体而受到阻碍。最近鉴定的一些假定的肠干细胞标记物显示不同的表达模式内的干细胞龛表明，多个祖细胞池共存。有趣的是，这些肠道祖细胞群体可能属于类似于造血系统的干细胞层次。在肠道干细胞生态位内定义类似的层次结构将使我们能够前瞻性地分离离散的群体，从而扩展我们对肠道干细胞动力学的了解。 我们的长期研究目标是了解在稳态和疾病中调节肠道干细胞行为的机制。为肠干细胞联盟的这项研究项目提出的研究旨在检验以下假设：肠干细胞或祖细胞的离散群体存在于正常组织和肠癌中的癌症干细胞中的层次结构中。研究，以解决这些目标的目的是定义祖细胞群体使用蛋白质表达模式的免疫组织化学分析和三维肠隐窝重建沿着分析细胞表面抗原表达的荧光激活细胞分选。此外，将产生针对隐窝内未分化细胞的新型单克隆抗体，以扩大有效分离肠祖细胞和干细胞的可用资源。分离肠干细胞离散池的能力对于促进我们对肠道生物学的理解至关重要，这对于理解，分类和治疗肠道疾病至关重要。 公共卫生相关性：解开肠道生物学并利用这些知识治疗肠道疾病的关键在于识别和分离成体肠道干细胞的能力。该项目旨在了解这种细胞的功能，将提供对这些干细胞不能正常发挥功能的疾病的深入了解，例如肠癌。这些研究有可能改善诊断、为定向治疗提供信息并设计肠道疾病的新疗法。

DESCRIPTION (provided by applicant): The existence of intestinal stem cells residing in an interactive niche has been well-accepted as the source of continual self-renewal of the intestinal epithelium. However, while other organ systems have appreciated substantial progress in identifying stem populations and exploiting this knowledge for therapeutic treatment of disease, advances in the intestinal stem cell field have been hampered by the inability to definitively identify, isolate, and grow the stem cell population. Recent identification of a number of putative intestinal stem cell markers displaying distinct expression patterns within the stem cell niche suggests that multiple progenitor pools co-exist. Intriguingly, these intestinal progenitor populations may belong to a stem cell hierarchy analogous to that in the well-characterized hematopoietic system. Defining a similar hierarchy within the intestinal stem cell niche will allow us to prospectively isolate discrete populations, thereby extending our knowledge of intestinal stem cell dynamics. Our long-range research goal is to understand the mechanisms regulating intestinal stem cell behavior in homeostasis and in disease. The studies proposed for this Research Project for the Intestinal Stem Cell Consortium are designed to test the hypothesis that discrete populations of intestinal stem or progenitor cells exist within a hierarchy in both normal tissue, and among cancer stem cells in intestinal cancer. Studies to address these goals are designed to define progenitor populations using protein expression patterns by immunohistochemical analyses and 3-dimensional intestinal crypt reconstruction along with profiling of cell surface antigen expression by fluorescence-activated cell sorting. Further, novel monoclonal antibodies against undifferentiated cells within the crypt will be generated to expand the available resources for effective isolation of intestinal progenitor and stem cells. The ability to isolate discrete pools of intestinal stem cells is critical for advancing our understanding of intestinal biology, which is paramount for understanding, classifying and treating intestinal disease. PUBLIC HEALTH RELEVANCE: The key to unlocking intestinal biology and harnessing this knowledge for treatment of intestinal disease lies in the ability to identify and isolate the adult intestinal stem cell. This project, designed to understand how this cell functions, will provide insight into diseases where these stem cells do not function properly, such as in intestinal cancer. These studies have the potential for improving diagnoses, informing directed treatment, and designing new therapies for intestinal disease.