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: 7785009
• 负责人: Hooman Troy Ghashghaei
• 金额: $ 32.27万
• 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/7785009
• 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; Myxoid cyst; 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）：本提案的目标是阐明中枢神经系统中成体干细胞生态位（SCN）的细胞和分子机制，该生态位在整个生命过程中都蕴藏着干细胞。 SCN 位于前室下区，源自成体干细胞的新生神经元通过头端迁移流 (RMS) 迁移到嗅球 (OB)，并分化为中间神经元。成人视交叉上核由星形胶质细胞和室管膜细胞组成，排列在新纹状体的心室表面。这两种细胞类型均源自外侧神经节隆起 (LGE) 的胚胎 SCN。一系列转录因子已被证明可以在发育中的 LGE 的不同区域内调节细胞命运。我们鉴定了叉头转录因子 (FOXJ1)，它在 LGE 的胚胎祖细胞亚群中表达，并在出生后 SCN 中持续表达。我们提出的研究将揭示 SCN 分化的新机制，以及它们在调节成体干细胞和出生后大脑神经发生中的伴随作用。现在已经明确，放射状胶质细胞及其星形细胞后代的时机和正确发育对于中枢神经系统的正常发育和功能至关重要。我们的研究正在揭示放射状胶质细胞子集在发育中的 LGE 中的作用，这可能会在嗅球中产生层特异性神经元的子集。虽然许多研究都集中在大脑皮质中放射状胶质细胞神经元后代的特化上，但介导室管膜细胞和星形胶质细胞子集建立成体 SCN 的特化的分子机制尚未被探索。全面了解这些机制非常有意义，因为它们对成体干细胞和/或出生后 SCN 的操纵可能会产生新的神经元，并引导神经元迁移到受损或患病的大脑区域，并可能纠正主要出生缺陷如脑积水。 公共健康相关性：我们提出的研究将确定驱动出生后和成体神经干细胞细胞生态位发育的基因的新调控机制。描述出生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细胞疗法中的应用至关重要。