Injury-Evoked Regeneration Mechanism in Olfactory System

嗅觉系统损伤诱发的再生机制

基本信息

批准号：
7425931
负责人：
COLLEEN Cosgrove HEGG
金额：
$ 24.29万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7425931
关键词：
Adult Afferent Neurons Agonist Apoptosis Autonomic nervous system Biological Assay Bioluminescence Cell Differentiation process Cell Proliferation Cell membrane Cell physiology Cells Complex Condition Confocal Microscopy Coupled Data Development Electric Capacitance Electrophysiology (science)Epithelial Event Exocytosis GTP-Binding Proteins Goals Growth Growth Factor Growth Factor Receptors Immunohistochemistry In Vitro Injury Knowledge Lead Localized Luciferases Measures Mediating Membrane Membrane Transport Proteins Microbe Monitor Mus Natural regeneration Nervous system structure Neuromodulator Neurons Neurotransmitters Nucleotides Odors Olfactory Epithelium Pathway interactions Peripheral Physiological Process Purinoceptor Receptor Activation Reporting Research Research Personnel Role Signal Transduction Source Stem cells Stimulation of Cell Proliferation Stimulus Supporting Cell System Testing Tissues Variant base cell injury cell type extracellular immunocytochemistry in vivo injured insight luciferin neuroepithelium neurogenesis neurotrophic factor novel pollutant programs repaired sustentacular cell therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The peripheral olfactory neuroepithelium is able to regenerate after injury; however the signals that initiate the complex cascade leading to increased cell proliferation and neurogenesis are poorly understood. We will examine ATP as an important local trophic factor in injury-evoked olfactory neuron regeneration. We hypothesize that noxious insult to the olfactory epithelium triggers an extracellular ATP-induced signaling cascade that initiates regeneration of the neuroepithelium. We base this hypothesis on the observation that (1) cell damage, iysis and also regulated processes will release ATP into the extracellular milieu and (2) activation of purinergic receptors induces synthesis and/or release of neurotrophic factors, mitogenesis, and differentiation in the CNS. Thus, ATP released by acutely injured cells could stimulate localized regeneration due to the mitogenic and growth-promoting effects of purinergic receptor activation. Growth promotion can be mediated by G protein coupled purinergic receptors located on sustentacular support cells and basal stem cells, which, like other growth factor receptors, induce a cascade of intracellular events that trigger cell proliferation. Our specific aims are to (1) Determine if noxious and physiological stimuli evoke release of ATP in the OE. We will identify toxicological and physiological stimuli, pathways of release and sources of ATP using bioluminescence assays and confocal microscopy. (2) Determine if extracellular ATP and purinergic receptor activation elicits the release of neurotrophic factors. We will measure ATP-induced increases in membrane capacitance as an indication of exocytosis, vesicular release of ATP, and release of neurotrophic factors using electrophysiology, confocal microscopy and immunocytochemistry. (3) Determine if extracellular ATP and activation of purinergic receptors elicits proliferation. We will determine if ATP is sufficient to initiate proliferation or acts synergistically to initiate proliferation in the uninjured olfactory epithelium, and/or promotes injury-evoked proliferation using immunohistochemistry and in vitro and in vivo assays. This data will clearly have implications for the pharmacological modulation of proliferation. Agents that modify the effects of purinergics and purinergic receptors are readily available and could therapeutically modulate cell proliferation and differentiation, in the olfactory system and in the CNS.

描述（由申请人提供）：受伤后的周围嗅觉神经上皮能够再生；但是，启动复杂级联反应导致细胞增殖和神经发生增加的信号知之甚少。我们将研究ATP是损伤引起的嗅觉神经元再生中重要的局部营养因子。我们假设对嗅觉上皮的有害侮辱会触发细胞外ATP诱导的信号传导级联反应，从而启动了神经上皮的再生。我们基于以下观察结果：（1）细胞损伤，ISSIS和受调节过程将ATP释放到细胞外环境中，并且（2）嘌呤能受体的激活可诱导CNS中的神经营养因子，有丝分裂因素和分化的神经营养因子的合成和/或释放。因此，由于嘌呤能受体激活的有丝分裂和生长促进作用，急性损伤细胞释放的ATP可能会刺激局部再生。促进生长可以通过位于棘突支撑细胞和基础干细胞上的G蛋白偶联受体介导的，与其他生长因子受体一样，它们会诱导一系列触发细胞增殖的细胞内事件。我们的具体目的是（1）确定是否有害和生理刺激引起了OE中ATP的释放。我们将使用生物发光测定和共聚焦显微镜确定毒理学和生理刺激，释放途径和ATP来源。（2）确定细胞外ATP和嘌呤能受体激活是否会引起神经营养因子的释放。我们将使用电生理学，共聚焦显微镜和免疫细胞化学化学方法来衡量ATP诱导的膜电容增加，作为胞吞作用，囊泡释放以及神经营养因子的释放。（3）确定细胞外ATP和嘌呤能受体的激活是否引起增殖。我们将确定ATP是否足以引发增殖或协同作用，以在未造成的嗅觉上皮中引发增殖，并使用免疫组织化学以及体外和体内分析来促进受伤引起的增殖。该数据显然对增殖的药理调节有影响。在嗅觉系统和中枢神经系统中，可以轻松获得改变嘌呤能和嘌呤能受体作用的药物。