The Intestinal Stem Cell Niche

描述(申请人提供)：干细胞的定义是长期自我更新的能力和多系特征。直到最近，我们对干细胞及其在人类疾病中的作用的了解还相当有限。此外，利用干细胞的自我更新能力来促进器官和组织再生的兴趣跨越了许多医学学科。现在人们认识到，我们必须更好地了解支持和定义干细胞的复杂遗传学和过程。这项建议是解决这一问题的一种多学科方法，将四名研究人员的科学优势以及机构核心设施和支持结合在一起，以研究肠道干细胞。最近，遗传学研究已经确定了肠道干细胞群体的强大标记。这些进展现在使得分离干细胞群体用于更先进的分子研究成为可能，它们也为我们提供了一个机会来研究疾病环境如何影响干细胞的活性和规格。干细胞高度依赖于对抗与细胞复制相关的众多压力的机制。在面对这样的挑战时，在维持基因组稳定性方面的缺陷会导致干细胞损失。如果这一过程得不到控制，可能会导致与年龄相关的退行性病变的过早发作。干细胞面临的另一个挑战是根据环境线索正确地确定它们的组织身份。干细胞鉴定的错误在食道和胃的肠化生以及许多胃肠癌中都会遇到。考虑到这些观察结果，我们建议检验以下假设：肠道干细胞的特性和活性可以受到细胞自主和非细胞自主过程的调节。这一假设将被以下相互关联的具体目标所追求：(1)体内骨髓来源细胞对肠道干细胞(ISC)生态位贡献的功能表征。(2)同源同源蛋白转录因子CDX2规定了干细胞的“肠道”特性。(3)开发新的策略来识别新的肠道干细胞标记物并分析干细胞功能。这项提议寻求利用我们的联合专业知识，以便更好地了解支持和指定肠道干细胞的分子事件。了解这些分子过程将极大地提高我们开发新的治疗策略的能力，以开发干细胞的再生潜力，以及纠正导致许多G1疾病的干细胞缺陷。 与公共卫生相关：干细胞对于肠道上皮的更新至关重要。许多人类疾病会影响干细胞的活性以及自我更新和分化的能力。这项建议探索了骨髓和基质元素对肠道干细胞生物学和生存的贡献，以及细胞自主机制。在这里学到的知识将在再生医学、衰老和癌症发生中得到应用。

DESCRIPTION (provided by applicant): Stem cells are defined by the capacity for long-term self-renewal and multilineage specification. Until recently, our understanding of stem cells, as well as their role in human diseases has been rather limited. Moreover, interest in harnessing the stem cell's capacity for self-renewal to promote organ and tissue regeneration traverses many medical disciplines. It is now recognized as imperative that we better understand the complex genetics and processes that support and define the stem cell. This proposal is a multidisciplinary approach to this problem, combining the scientific strengths of four investigators, as well as institutional core core facilities and support into a cohesive approach to study the intestinal stem cell. Recently, genetic studies have identified robust markers for stem cell populations in the intestine. These advances now make it possible to isolate stem cell populations for more advanced molecular investigations They also provide us an opportunity to study how disease environments impact upon stem cell viability and specification. Stem cells are highly reliant upon mechanisms to counter the numerous stresses associated with cellular replication. Defects in maintaining genome stability in the face of such challenges cause stem cell losses. If this process is unchecked, it can lead to the premature onset of age-related degenerative pathologies. Another challenge encountered by stem cells is to correctly determine their tissue identity based upon environmental cues. Errors in stem cell identity are encountered in intestinal metaplasia of the esophagus and stomach, as well as many gastrointestinal cancers. With these observations in mind, we propose to test the following hypothesis: Intestinal stem cell identity and viability can be modulated by cell-autonomous and non-cell autonomous processes. This hypothesis will be pursued by the following interrelated Specific Aims: (1) Functional characterization of the contribution by bone-marrow derived cells to the intestinal stem cell (ISC) niche in vivo. (2) The homeodomaln transcription factor Cdx2 specifies the stem cell's "intestinal" identity. (3) Develop novel strategies to identify new intestinal stem cell markers and assay stem cell functions. This proposal seeks to exploit our combined expertise in order to better understand the molecular events that support and specify intestinal stem cells. Understanding these molecular processes will greatly improve our ability to develop novel therapeutic strategies to exploit the regenerative potential of stem cells, as well as correct stem cell deficiencies that contribute to many Gl diseases. PUBLIC HEALTH RELEVANCE: Stem cells are critical for the renewal of the intestinal epithelium. Many human diseases can affect stem cell viability and capacity for self-renewal and differentiation. This proposal explores contributions to intestinal stem cell biology and survival by bone-marrow and stromal elements, as well as cell-autonomous mechanisms. Knowledge gained here will have applications for regenerative medicine, aging, and carcinogenesis.