Specification of Peripheral Olfactory Stem Cells

外周嗅觉干细胞的规格

• 批准号: 8912894
• 负责人: ANTHONY S LAMANTIA
• 金额: $ 33.34万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912894
• 关键词: Accounting; Adult; Afferent Neurons; Alzheimer' s Disease; Autistic Disorder; Basal Cell; Biological; Cells; Characteristics; Code; Consensus; DNA Binding; Data; Disease; Embryo; Environmental Exposure; Feeding behaviors; Foundations; Genes; Genetic; Genetic Transcription; Gonadotropin Hormone Releasing Hormone; Hypothalamic structure; In Vitro; Investigation; Life; Mediating; Mental disorders; Molecular; Molecular Genetics; Monitor; Mutate; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neurosecretory Systems; Olfactory Epithelium; Parkinson Disease; Pathology; Peripheral; Population; Publishing; Recording of previous events; Regulation; Reproduction; Reproductive Behavior; Role; Schizophrenia; Sensory; Signal Transduction; Site; Smell Perception; Social Behavior; Social Interaction; Source; Stem cells; Supporting Cell; Toxic effect; Transcriptional Regulation; Tretinoin; Variant; base; defined contribution; feeding; histogenesis; in vivo; insight; nerve stem cell; nervous system disorder; neurogenesis; neuronal replacement; progenitor; receptor; relating to nervous system; research study; self-renewal; stem; stem cell niche; tissue repair; transcription factor

ABSTRACT Stem cells in the embryonic vertebrate olfactory epithelium (OE) generate critical peripheral chemosensory and central neuroendocrine neurons-essential for feeding, social interactions, and reproduction. Nevertheless, mechanisms for establishing and maintaining these embryonic OE stem cells remain unknown. The progeny of embryonic OE stem cells are retained as progenitors throughout life to constantly replace OE chemosensory neurons; however the relationship between embryonic and adult OE stem cells is largely unexplored. We have recently defined apparent stem and transit amplifying cell populations in the embryonic OE. Apparent embryonic OE stem cells express high levels of the transcription factor Meis1 as well as low levels of Sox2, divide slowly and symmetrically, and are necessary for the genesis of olfactory and vomeronasal receptor neurons (ORNs, VRNs) and gonadotropin releasing hormone (GnRH) neurons-the OE neuronal lineage. The apparent transit amplifying cells express neurogenic bHLH genes including Ascl1 as well as high levels of Sox2, undergo rapid terminal neurogenic divisions, and expand numbers of ORNs, VRNs and GnRH neurons. We will now establish transcription regulatory and signaling mechanisms that determine the identity, proliferative capacity, and progression of OE stem or transit amplifying cells through the OE neurogenic lineage. We will determine how embryonic OE stem or transit amplifying cells with distinct transcriptional and signaling histories give rise to precursor populations established in the embryonic OE and retained in the adult to generate ORNs and VRNs throughout life. Specific Aim 1 will define differential influences of transcriptional regulators on OE stem versus transit amplifying cells. Specific Aim 2 will establish molecular mechanisms that underlie a transcription regulatory network essential for OE stem cell identity and lineage progression. Specific Aim 3 will establish the role of local signaling in defining and maintaining a niche for embryonic OE stem cells. Specific Aim 4 will relate the identity of subsets of embryonic OE stem and transit amplifying cells to adult OE progenitor populations. Our experiments therefore provide a mechanistic account of how OE stem cells are established, and how they are regulated to generate ORNs, VRNs and GnRH neurons. The data provide insight into how stem cells in specific niches mediate histogenesis and tissue repair. Our investigation of molecular mechanisms underlying OE stem cell regulation will also identify potential targets for degenerative change associated with diminished olfaction in a number of neurological and psychiatric disorders including Parkinson's and Alzheimer's diseases as well as schizophrenia.

抽象的 胚胎脊椎动物嗅觉上皮（OE）中的干细胞会产生关键的外周化学感应和 中央神经内分泌神经元，这些神经元必不可少，用于喂养，社交互动和繁殖。尽管如此， 建立和维持这些胚胎OE干细胞的机制尚不清楚。后代 胚胎OE干细胞在一生中保留为祖细胞，以不断替代OE化学感应 神经元；但是，胚胎和成年OE干细胞之间的关系在很大程度上尚未探索。我们有 最近定义的明显的茎和传输扩增了胚胎OE中的细胞群。显而易见 胚胎OE干细胞表达高水平的转录因子Meis1以及低水平的Sox2， 缓慢而对称地分裂，对于嗅觉和呕吐受体的起源是必不可少的 神经元（ORNS，VRN）和促性腺激素释放激素（GNRH）神经元 - OE神经元谱系。这 明显的传输放大细胞表达神经源性BHLH基因，包括ASCL1以及高水平 SOX2，经历快速的末端神经源性分裂，并扩大了ORN，VRN和GNRH神经元的数量。 现在，我们将建立确定身份的转录调节和信号传导机制 OE茎或Transit扩增细胞的增殖能力以及通过OE神经源的进展 血统。我们将确定胚胎OE茎或过境的分化细胞如何具有独特的转录和 信号传导历史引起了在胚胎OE中建立并保留在成人中的前体种群 一生都会产生ORN和VRN。特定目标1将定义转录的差异影响 OE茎上的调节剂与传输的放大细胞。特定目标2将建立分子机制 基于OE干细胞同一性和谱系进展至关重要的转录调节网络。具体的 AIM 3将确定局部信号在定义和维持胚胎干细胞的利基市场中的作用。 特定的目标4将关联胚胎OE茎的子集的身份，并将其放大细胞与成年OE 祖先种群。因此，我们的实验提供了OE干细胞如何的机理说明 建立，以及如何调节它们以产生ORN，VRN和GNRH神经元。数据提供 深入了解特定壁ches中的干细胞如何介导组织发生和组织修复。我们的调查 OE干细胞调节的分子机制还将确定退化的潜在靶标 与许多神经和精神疾病有关的嗅觉减少相关的变化 帕金森氏症和阿尔茨海默氏症的疾病以及精神分裂症。