Remodeling the epithelial stem cell

重塑上皮干细胞

• 批准号: 7634505
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 22.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-06 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7634505
• 关键词: ATPase Domain; Adopted; Adult; Affect; Biological; Cells; Chromatin; Chromatin Structure; Cues; Data; Development; Embryo; Embryonic Development; Enzymes; Epidermis; Epigenetic Process; Epithelial; Erythroid; Gene Expression; Genes; Genetic; Goals; Hair; Hair follicle structure; Hair shaft structure; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; In Situ; Individual; Integumentary system; Laboratories; Life; Lymphoid; Maintenance; Methods; Molecular; Molecular Profiling; Molecular Target; Myelogenous; Natural regeneration; Pathway interactions; Play; Population; Property; Regulation; Role; Signal Transduction; Site; Staging; Stem cells; System; Techniques; Tissues; Work; adult stem cell; cell behavior; cell type; chromatin remodeling; embryonic stem cell; gene function; insight; keratinocyte; mutant; pluripotency; progenitor; self-renewal; stem cell biology; stem cell differentiation; stem cell population; stemness

DESCRIPTION (provided by applicant): We have recently shown that the chromatin remodeler Mi-2b is critical for the self-renewal properties of the hematopoietic stem cell (HSC) and for the plasticity that allows its progeny to differentiate along the various lineages of the hematopoietic system. We now propose to extend this analysis to the stem cells of the hair follicle whose unique properties allow rigorous analysis of gene function in these cells and their derivatives. Our preliminary data show that Mi-2b is necessary for maintenance of the hair follicle in the adult. We will now exploit existing methods to delete Mi-2b specifically in two distinct follicular stem cell populations, the long-lived follicular bulge stem cell and the short-lived matrix stem cell. This approach will be augmented by techniques newly developed in the laboratory to target and purify these distinct stem cell types. We will characterize the effects of deleting Mi-2b in these populations and the molecular pathways affected. By comparing these with results already obtained in the hematopoietic system, we will gain insight into the common genetic cascades that control adult somatic stem cell behavior. Enzymes that remodel chromatin to regulate the accessibility of genes play a critical role in adult stem cells both by poising some genes for potential expression and by actively repressing the expression of others. We have previously demonstrated the role of the chromatin remodeler Mi-2b in the maintenance of the hematopoietic stem cell and differentiation of its progeny and identified the genes regulated in these cells. We propose to characterize the requirement for Mi-2b in another adult stem cell population, the keratinocyte stem cells of the adult hair follicle. By comparing the function of Mi-2b in these two different stem cells, we hope to identify common functions that are fundamental to stem cell behavior while identifying activities that are specific to these different types of stem cells.

描述（由申请人提供）：我们最近表明，染色质重塑剂 Mi-2b 对于造血干细胞 (HSC) 的自我更新特性以及允许其后代沿着造血系统的各种谱系分化的可塑性至关重要。我们现在建议将这种分析扩展到毛囊干细胞，其独特的特性允许对这些细胞及其衍生物的基因功能进行严格分析。我们的初步数据表明，Mi-2b 对于维持成人毛囊是必需的。现在，我们将利用现有方法，专门删除两种不同的毛囊干细胞群体（长寿命的毛囊隆起干细胞和短寿命的基质干细胞）中的 Mi-2b。这种方法将通过实验室新开发的技术得到增强，以靶向和纯化这些不同的干细胞类型。我们将描述删除 Mi-2b 对这些群体的影响以及受影响的分子途径。通过将这些结果与造血系统中已获得的结果进行比较，我们将深入了解控制成体干细胞行为的常见遗传级联。重塑染色质以调节基因可及性的酶在成体干细胞中发挥着关键作用，它们既可以平衡某些基因的潜在表达，又可以主动抑制其他基因的表达。我们之前已经证明了染色质重塑剂 Mi-2b 在造血干细胞的维持及其后代分化中的作用，并鉴定了这些细胞中受调节的基因。我们建议描述另一个成体干细胞群（成体毛囊的角质形成细胞干细胞）对 Mi-2b 的需求。通过比较 Mi-2b 在这两种不同干细胞中的功能，我们希望确定干细胞行为基础的共同功能，同时确定这些不同类型干细胞特有的活性。