Improving olfactory neuroplasticity through FAK/CNTF signaling

通过 FAK/CNTF 信号传导改善嗅觉神经可塑性

• 批准号: 10504028
• 负责人: Cuihong Jia
• 金额: $ 37.17万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504028
• 关键词: 2019-nCoV; Acute; Adult; Aging; Anosmia; Autocrine Communication; Axon; Basal Cell; Behavioral; Behavioral Genetics; Blunt Head Injuries; COVID-19; Cell Proliferation; Cell Separation; Cells; Chronic; Ciliary Neurotrophic Factor; Ciliary Neurotrophic Factor Receptor; Clinical; Craniocerebral Trauma; Data; Dose; Failure; Female; Focal Adhesion Kinase 1; Genetic; Genetic Transcription; Goals; Grant; Health; Human; IL6ST gene; In Vitro; Infection; Inflammation; Injury; Integrins; Intranasal Administration; JNK-activating protein kinase; Knockout Mice; MAPK8 gene; Measures; Mediating; Methimazole; Methods; Modeling; Molecular; Mus; Nervous system structure; Neuronal Plasticity; Olfactory Epithelium; Olfactory Nerve; Olfactory dysfunction; Paracrine Communication; Pathway interactions; Pharmacology; Production; Proliferating; Quality of life; Recovery; Recovery of Function; Reporter; Role; Safety; Signal Transduction; Smell Perception; TNF gene; Testing; Therapeutic; Virus Diseases; axon growth; behavior test; cancer clinical trial; chronic rhinosinusitis; cytokine; epithelial injury; hyposmia; improved; in vivo; inhibitor; kinase inhibitor; male; mouse model; nerve stem cell; neurogenesis; neutralizing antibody; new therapeutic target; novel; olfactory bulb; olfactory neurogenesis; olfactory sensory neurons; receptor; reconstitution; reinnervation; response; side effect; stem cells

Project Summary Olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) are continuously replaced from basal stem cells and grow their axons to the olfactory bulb to maintain the sense of smell. Failure to reconstitute the OE after injury, infection or aging, causes olfactory dysfunction which is a safety and a quality of life issue. No treatments are available. Defining the signals that regulate olfactory neuroplasticity would reveal new therapeutic targets to improve olfactory deficits. Ciliary neurotrophic factor (CNTF) is highly expressed in horizontal basal cells (HBCs) and olfactory ensheathing cells (OECs), while the CNTFRα receptor is expressed in the neighboring neuronal progenitor globose basal cells (GBCs). We found that CNTF is suppressed by focal adhesion kinase (FAK) and that intranasal application of an FAK inhibitor promotes OE neurogenesis via CNTF. Importantly, FAK inhibitor further enhances CNTF expression caused by OE injury with methimazole. We will use genetic, pharmacological, and behavioral approaches in male and female mice to test the hypothesis that FAK inhibition promotes olfactory neuroplasticity following injury by increasing CNTF expression. Aim 1 will define the FAK-CNTF-CNTFRα pathway underlying GBC proliferation by first determining whether FAK inhibition induces CNTF in HBCs, OECs or both. We will also determine whether CNTF is released to activate CNTFRα signaling in stimulating GBC proliferation, and whether FAK inhibition acts through this intercellular mechanism. To increase the relevance of our findings, Aim 2 will determine whether FAK inhibition can increase olfactory neurogenesis via CNTF following acute OE injury. Thus, we will use acute injury with methimazole and determine whether injury increases CNTF in HBCs and/or OECs which leads to increased GBC proliferation and neurogenesis. The effect of FAK inhibitor treatment following methimazole may be within HBCs and/or OECs, something we will test. To prepare for additional studies, we will define an optimal dose of FAK inhibitor and then test whether CNTF mediates the effect of FAK inhibitor to promote OE neurogenesis after acute injury. Chronic olfactory inflammation inhibits HBC proliferation and increases FAK signaling in HBCs, suggesting that CNTF might be suppressed. To broaden the relevance to more types of olfactory injuries, Aim 3 will use a refined chronic olfactory inflammation mouse model to determine whether FAK inhibition increases CNTF and promotes GBC proliferation and olfactory neurogenesis. Aim 4 will determine the ability of FAK inhibition to promote OSN axonal growth and olfactory function recovery following acute and chronic types of OE injury, using genetic axon tracing methods combined with behavioral tests. This proposal will define the role of FAK and CNTF and validate the therapeutic potential of FAK inhibitors to improve olfactory function after injury. FAK inhibitors are well-tolerated in cancer clinical trials and intranasal administration avoids systemic side effects.

项目摘要 嗅觉上皮（OE）中的嗅觉感觉神经元（OSN）连续地从碱性茎中取代 细胞并将其轴突生长到嗅球以保持嗅觉。未能重建OE 受伤，感染或衰老后，会引起嗅觉功能障碍，这是一种安全性和生活质量问题。不 可以治疗。定义调节嗅觉神经可塑性的信号将显示新的 改善嗅觉缺陷的治疗靶标。睫状神经营养因子（CNTF）高度表达 水平基线细胞（HBCS）和嗅觉分类细胞（OEC），而CNTFRα受体表示 在邻近的神经祖细胞球体碱性细胞（GBC）中。我们发现CNTF被抑制 局灶性粘合剂激酶（FAK）和鼻内施用FAK抑制剂可通过 CNTF。重要的是，FAK抑制剂进一步增强了由甲咪唑损伤引起的CNTF表达。 我们将在雄性和雌性小鼠中使用遗传，药物和行为方法来测试 假设FAK抑制作用通过增加CNTF而促进损伤后嗅觉神经可塑性 表达。 AIM 1将首先定义FAK-CNTF-CNTFRα途径GBC增殖的途径 确定FAK抑制是在HBC，OEC还是两者中诱导CNTF。我们还将确定是否 释放CNTF以激活刺激GBC增殖中的CNTFRα信号，以及是否FAK抑制 通过这种细胞间机制起作用。为了增加我们发现的相关性，AIM 2将决定 急性OE损伤后，FAK抑制是否会通过CNTF增加嗅觉神经发生。那我们会的 用甲咪唑使用急性损伤，并确定损伤是否会增加HBC和/或OEC中的CNTF 导致GBC增殖和神经发生增加。 FAK抑制剂治疗的影响 甲胺唑可能在HBC和/或OEC中，我们将测试。为了准备其他研究，我们 将定义最佳剂量的FAK抑制剂，然后测试CNTF是否介导FAK抑制剂对 急性损伤后促进OE神经发生。慢性嗅觉感染抑制了HBC的增殖和 增加了HBC中的FAK信号传导，表明CNTF可能会被抑制。扩大与 更多类型的嗅觉损伤，AIM 3将使用精致的慢性嗅觉损伤鼠标模型 确定FAK抑制是否会增加CNTF并促进GBC增殖和嗅觉 神经发生。 AIM 4将确定FAK抑制促进OSN轴突生长和嗅觉的能力 使用遗传轴突追踪方法合并急性和慢性OE损伤后的功能恢复 进行行为测试。该建议将定义FAK和CNTF的作用，并验证治疗潜力 FAK抑制剂的损伤后改善嗅觉功能。 FAK抑制剂在癌症临床上耐受性良好 试验和鼻内给药避免了全身副作用。