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-对摄食、社会互动和生殖至关重要。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干细胞的后代在整个生命过程中作为祖细胞保留，以不断取代OE化学感受神经元;然而，胚胎和成人OE干细胞之间的关系在很大程度上未被探索。我们最近定义了明显的干细胞和过境放大细胞群体在胚胎OE。明显的胚胎OE干细胞表达高水平的转录因子Meis 1以及低水平的Sox 2，分裂缓慢和对称，是必要的嗅觉和犁鼻受体神经元（ORN，VRNs）和促性腺激素释放激素（GnRH）神经元的OE神经元谱系的发生。表观转运放大细胞表达神经源性bHLH基因，包括Ascl 1以及高水平的Sox 2，进行快速的终末神经源性分裂，并扩增ORN、VRNs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，确定身份，增殖能力，和通过OE神经源性谱系的OE干细胞或过境扩增细胞的进展。我们将确定胚胎OE干细胞或转运扩增细胞与不同的转录和信号的历史产生的前体群体建立在胚胎OE和保留在成人产生ORN和VRNs在整个生命。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差异影响。具体目标2将建立一个转录调控网络的基础上OE干细胞的身份和谱系进展的分子机制。具体目标3将建立在定义和维持胚胎OE干细胞的小生境的局部信号的作用。具体目标4将使胚胎OE干细胞和转运扩增细胞的亚群的身份与成人OE祖细胞群体相关。因此，我们的实验提供了OE干细胞是如何建立的机制，以及它们是如何被调节以产生ORN，VRN和GnRH神经元的。这些数据提供了深入了解干细胞如何在特定的壁龛介导组织发生和组织修复。我们对OE干细胞调节的分子机制的研究也将确定与一些神经和精神疾病（包括帕金森病和阿尔茨海默病以及精神分裂症）中嗅觉减弱相关的退行性变化的潜在靶点。 公共卫生相关性：嗅上皮（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，以制造对嗅觉，进食，社会互动和生殖至关重要的神经元。这些干细胞可能在几种神经退行性疾病中受损，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干细胞的分子机制，调节嗅觉神经元的终身发生，并且可能是神经和精神疾病的致病靶点。