The Intestinal Stem Cell Niche

肠道干细胞利基

• 批准号: 7791550
• 负责人: JOHN P. LYNCH
• 金额: $ 39.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791550
• 关键词: 3-Dimensional; Affect; Aging; Apoptosis; Atrophic; Biological Assay; Biopsy; Bone Marrow; Bone Marrow Transplantation; Cell Culture System; Cell Maintenance; Cell Proliferation; Cell Survival; Cell model; Cell physiology; Cells; Cellular biology; Complex; Core Facility; Cues; Data; Defect; Discipline; Disease; Elements; Environment; Epithelial; Epithelial Cells; Esophagus; Event; Face; Genetic; Genetic Markers; Genetic Processes; Genome Stability; Human; In Vitro; Intestinal Metaplasia; Intestines; Investigation; Knowledge; Lead; Malignant neoplasm of gastrointestinal tract; Medical; Methodology; Methods; Mind; Modeling; Molecular; Organ; Pathology; Play; Process; Property; Regenerative Medicine; Reporting; Research Personnel; Role; Specific qualifier value; Specificity; Stem cells; Stomach; Stress; Techniques; Telomerase; Testing; Tissues; Work; age related; base; carcinogenesis; daughter cell; dosage; experience; homeodomain; human disease; improved; in vivo; interdisciplinary approach; interest; intestinal crypt; intestinal epithelium; mouse model; novel; novel strategies; novel therapeutics; premature; programs; public health relevance; regenerative; self-renewal; stem cell biology; stem cell niche; stem cell population; success; tissue regeneration; transcription factor

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.

描述（由申请人提供）：干细胞由长期自我更新和多列纳格规范的能力定义。直到最近，我们对干细胞及其在人类疾病中的作用的理解一直受到限制。此外，有兴趣利用干细胞自我更新促进器官和组织再生的能力遍历许多医学学科。现在认为，我们必须更好地了解支持和定义干细胞的复杂遗传和过程。该建议是解决此问题的一种多学科方法，结合了四个研究者的科学优势，以及制度性的核心设施和支持，以研究肠道干细胞的凝聚力方法。最近，遗传研究已经确定了肠道中干细胞群体的鲁棒标记。现在，这些进步使得分离干细胞种群进行更先进的分子研究成为可能，它们还为我们提供了研究疾病环境如何影响干细胞生存能力和规范的机会。干细胞高度依赖于应对与细胞复制相关的众多应力的机制。面对此类挑战的维持基因组稳定性的缺陷会导致干细胞损失。如果该过程未经检查，则可能导致与年龄相关的退行性病理的过早发作。干细胞遇到的另一个挑战是根据环境提示正确确定其组织身份。在食道和胃的肠道上以及许多胃肠道癌症中遇到了干细胞同一性的错误。考虑到这些观察，我们建议检验以下假设：肠道干细胞的身份和活力可以通过细胞自主和非细胞自主过程调节。该假设将通过以下相互关联的特定目的来提出：（1）骨髓衍生细胞对体内肠道干细胞（ISC）壁s的贡献的功能表征。 （2）谱系转录因子CDX2指定了干细胞的“肠道”身份。 （3）制定新的策略来鉴定新的肠道干细胞标记和测定干细胞功能。该建议旨在利用我们的组合专业知识，以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型治疗策略来利用干细胞再生潜力的能力，以及正确的干细胞缺陷，这些缺乏有助于许多GL疾病。 公共卫生相关性：干细胞对于肠上皮的更新至关重要。许多人类疾病会影响干细胞活力和自我更新和分化的能力。该提案探讨了骨髓和基质元素以及细胞自治机制对肠道干细胞生物学和生存的贡献。这里获得的知识将在再生医学，衰老和癌变中应用。