Characterization of intestinal stem cells (research project)

描述（由申请人提供）：肠道干细胞存在于相互作用的生态位中，已被广泛接受为肠道上皮持续自我更新的来源。然而，尽管其他器官系统在识别干细胞群体和利用这些知识进行疾病治疗方面取得了实质性进展，但肠道干细胞领域的进展却受到无法明确识别、分离和培养干细胞群体的阻碍。最近发现的一些肠道干细胞标记物在干细胞生态位中表现出不同的表达模式，这表明多个祖细胞池共存。有趣的是，这些肠道祖细胞群可能属于一个干细胞等级，类似于具有良好特征的造血系统。在肠道干细胞生态位中定义类似的层次结构将使我们能够前瞻性地分离离散种群，从而扩展我们对肠道干细胞动力学的了解。

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.