Specification of Peripheral Olfactory Stem Cells

外周嗅觉干细胞的规格

• 批准号: 8247915
• 负责人: ANTHONY S LAMANTIA
• 金额: $ 33.68万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8247915
• 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; Wound Healing; 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; transcription factor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Neural stem cells in the olfactory epithelium (OE) arise in the embryo and are retained throughout life to make neurons that are essential for smell, feeding, social interactions and reproduction. These stem cells may be compromised in several neurodegenerative conditions in which olfactory deficits are early indicators of disease. This project will identify molecular mechanisms that define embryonic OE stem cells, regulate lifelong genesis of olfactory neurons, and are likely pathogenic targets for neurological and psychiatric diseases.

描述（由申请人提供）：胚胎脊椎动物嗅上皮（OE）中的干细胞产生关键的外周化学感觉和中枢神经内分泌神经元——对于进食、社交互动和繁殖至关重要。然而，建立和维持这些胚胎 OE 干细胞的机制仍然未知。胚胎OE干细胞的后代作为祖细胞终生保留，不断替代OE化学感应神经元；然而，胚胎和成体 OE 干细胞之间的关系很大程度上尚未被探索。我们最近在胚胎 OE 中定义了表观干细胞和转运扩增细胞群。表观胚胎 OE 干细胞表达高水平的转录因子 Meis1 和低水平的 Sox2，分裂缓慢且对称，对于嗅觉和犁鼻受体神经元 (ORN、VRN) 和促性腺激素释放激素 (GnRH) 的发生是必需的神经元-OE神经元谱系。明显的转运放大细胞表达神经源性 bHLH 基因，包括 Ascl1 以及高水平的 Sox2，经历快速的终末神经源性分裂，并扩大 ORN、VRN 和 GnRH 神经元的数量。我们现在将建立转录调控和信号传导机制，以确定 OE 干细胞或转运放大细胞通过 OE 神经源性谱系的身份、增殖能力和进展。我们将确定具有不同转录和信号传导历史的胚胎 OE 干细胞或转运放大细胞如何产生在胚胎 OE 中建立并保留在成体中的前体群体，从而在整个生命过程中产生 ORN 和 VRN。具体目标 1 将定义转录调节因子对 OE 干细胞与转运扩增细胞的不同影响。具体目标 2 将建立对 OE 干细胞身份和谱系进展至关重要的转录调控网络基础的分子机制。具体目标 3 将确定局部信号传导在定义和维持胚胎 OE 干细胞生态位中的作用。具体目标 4 将胚胎 OE 干细胞和转运扩增细胞亚群的身份与成年 OE 祖细胞群联系起来。因此，我们的实验提供了 OE 干细胞如何建立以及如何调节它们产生 ORN、VRN 和 GnRH 神经元的机制解释。这些数据让我们深入了解特定生态位中的干细胞如何介导组织发生和组织修复。我们对 OE 干细胞调节分子机制的研究还将确定与许多神经和精神疾病（包括帕金森病、阿尔茨海默病以及精神分裂症）嗅觉减弱相关的退行性变化的潜在目标。 公共健康相关性：嗅觉上皮 (OE) 中的神经干细胞在胚胎中产生，并在整个生命过程中保留，以形成对嗅觉、进食、社交互动和繁殖至关重要的神经元。这些干细胞可能会在几种神经退行性疾病中受到损害，其中嗅觉缺陷是疾病的早期指标。该项目将确定定义胚胎 OE 干细胞、调节嗅觉神经元终生发生以及可能成为神经和精神疾病致病靶点的分子机制。