Transcriptional regulation of aging in the adult neural stem cell niche

成体神经干细胞生态位衰老的转录调控

• 批准号: 8234492
• 负责人: Hooman Troy Ghashghaei
• 金额: $ 5万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-18 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234492
• 关键词: Address; Adult; Aging; Anterior; Astrocytes; Birth; Brain; Brain region; Cell Line; Cell Therapy; Cell physiology; Cells; Cerebral cortex; Characteristics; Congenital Abnormality; Data; Development; Embryo; Ependymal Cell; Exhibits; Future; Ganglia; Generations; Genes; Genetic; Goals; Harvest; Head; Homeostasis; Hydrocephalus; In Vitro; Interneurons; Knockout Mice; Lateral; Life; Light; Mediating; Molecular; Neostriatum; Neuroglia; Neurons; Population; Production; Prosencephalon; Radial; Regulation; Role; Specific qualifier value; Stem cells; Stream; Structure; Surface; Testing; Time; Transcriptional Regulation; Ventricular; adult neurogenesis; adult stem cell; base; cell type; cellular development; embryonic stem cell; forkhead protein; interest; lateral ventricle; loss of function; migration; nerve stem cell; neurogenesis; novel; olfactory bulb; postnatal; prenatal; progenitor; promoter; public health relevance; stem cell niche; subventricular zone; tool; transcription factor

DESCRIPTION (provided by applicant): The goal of this proposal is to elucidate cellular and molecular mechanisms that specify the adult stem cell niche (SCN) in the CNS that harbors stem cells throughout life. The SCN is situated in the anterior subventricular zone where newly born neurons derived from adult stem cells migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) and differentiate into interneurons. The adult SCN consists of astrocytes and ependymal cells that line the ventricular surface of the neostriatum. Both these cell types are derived from an embryonic SCN in the lateral ganglion eminences (LGE). A constellation of transcription factors have been shown to regulate cell fate within distinct domains of the developing LGE. We have identified a fork head transcription factor (FOXJ1) which we show is expressed in a subset of embryonic progenitors in the LGE, and exhibits persistent expression in the postnatal SCN. Our proposed studies will shed light on novel mechanisms underlying differentiation of the SCN, and their concomitant role in regulation of adult stem cells and neurogenesis in the postnatal brain. It is now well established that the timing and proper development of radial glia and their astrocytic progeny are essential for normal CNS development and function. Our studies are unraveling the role of a subset of radial glial cells in the developing LGE which may give rise to a subset of layer specific neurons in the olfactory bulb. While a number of studies have focused on specification of neuronal progeny of radial glial cells in the cerebral cortices, molecular mechanisms that mediate the specification of ependymal cells and a subset of astrocytes that establish the adult SCN are completely unexplored. A comprehensive understanding of these mechanisms is of great interest as their manipulation in adult stem cells and/or the postnatal SCN may allow for production of new neurons and generation of guided neuronal migration to damaged or diseased brain regions, and potential correction of major birth defects such as hydrocephalus. PUBLIC HEALTH RELEVANCE: Our proposed studies will determine novel regulatory mechanisms of a gene that drives the development of a cellular niche for postnatal and adult neural stem cells. Delineation of mechanisms that regulate persistence of regionally specific neurogenesis in the postnatal and adult brain is critical to future application of adult neural stem cells in cell-based therapies.

描述（由申请人提供）：该提案的目的是阐明在CNS中指定成年干细胞生态位（SCN）的细胞和分子机制，这些机制在一生中携带了干细胞。 SCN位于室内下区域，该区域是源自成年干细胞的新生神经元，该神经元通过延髓迁移流（RMS）迁移到嗅球（OB）并分化为中间神经元。成年SCN由在新纹状体的心室表面排列的星形胶质细胞和室系室细胞组成。这两种细胞类型均来自外侧神经节e（LGE）中的胚胎SCN。已显示转录因子的星座可以调节发育中LGE不同域内的细胞命运。我们已经确定了我们显示的叉头转录因子（FOXJ1），该因子在LGE中的胚胎祖细胞的子集中表达，并在产后SCN中表现出持久的表达。我们提出的研究将阐明SCN分化的基本机制，以及它们在调节成年干细胞的作用以及产后大脑中神经发生的作用。现在可以很好地确定，径向神经胶质及其星形胶质细胞后代的时间和正常发育对于正常的中枢神经系统发育和功能至关重要。我们的研究揭示了径向神经胶质细胞在发育中的LGE中的作用，这可能会导致嗅球中特定层特异性神经元的子集。虽然许多研究集中在脑皮质中径向神经胶质细胞的神经元后代的规范上，但介导di介demandymal细胞规范的分子机制和确定成年SCN的星形胶质细胞的子集是完全未经探索的。对这些机制的全面理解引起了人们的极大兴趣，因为它们在成年干细胞和/或产后SCN中的操纵可能允许产生新的神经元，并产生引导的神经元迁移到受损或患病的大脑区域，并潜在地纠正诸如脑力头脑的主要出生缺陷。 公共卫生相关性：我们提出的研究将确定一种基因的新调节机制，该基因驱动了出生后和成人神经干细胞的细胞生态位。划定在产后和成人大脑中调节区域特异性神经发生持续性的机制对于未来成人神经干细胞在基于细胞的疗法中的应用至关重要。