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.

项目概要 嗅觉上皮 (OE) 中的嗅觉感觉神经元 (OSN) 不断从基底干中被替换 细胞并将其轴突生长到嗅球以维持嗅觉。无法重构 OE 受伤、感染或衰老后，会导致嗅觉功能障碍，这是一个安全和生活质量问题。不 可以进行治疗。定义调节嗅觉神经可塑性的信号将揭示新的 改善嗅觉缺陷的治疗目标。睫状神经营养因子（CNTF）在 水平基底细胞 (HBC) 和嗅鞘细胞 (OEC)，同时表达 CNTFRα 受体 在邻近的神经元祖球基底细胞（GBC）中。我们发现 CNTF 被抑制 粘着斑激酶 (FAK) 和 FAK 抑制剂的鼻内应用通过促进 OE 神经发生 CNTF。重要的是，FAK 抑制剂进一步增强了甲巯咪唑 OE 损伤引起的 CNTF 表达。 我们将在雄性和雌性小鼠中使用遗传、药理学和行为方法来测试 假设 FAK 抑制通过增加 CNTF 来促进损伤后的嗅觉神经可塑性 表达。目标 1 将首先定义 GBC 增殖背后的 FAK-CNTF-CNTFRα 途径 确定 FAK 抑制是否会诱导 HBC、OEC 或两者中的 CNTF。我们还将确定是否 CNTF 被释放以激活 CNTFRα 信号传导刺激 GBC 增殖，以及 FAK 抑制是否 通过这种细胞间机制发挥作用。为了提高我们研究结果的相关性，目标 2 将确定 FAK 抑制是否可以在急性 OE 损伤后通过 CNTF 增加嗅觉神经发生。这样，我们将 使用甲硫咪唑进行急性损伤，并确定损伤是否会增加 HBC 和/或 OEC 中的 CNTF，这 导致 GBC 增殖和神经发生增加。 FAK抑制剂治疗后的效果 他巴唑可能存在于 HBC 和/或 OEC 中，我们将对其进行测试。为了准备进一步的研究，我们 将确定FAK抑制剂的最佳剂量，然后测试CNTF是否介导FAK抑制剂的作用 促进急性损伤后的OE神经发生。慢性嗅觉炎症抑制 HBC 增殖 增加 HBC 中的 FAK 信号传导，表明 CNTF 可能受到抑制。扩大相关性 更多类型的嗅觉损伤，Aim 3将使用精致的慢性嗅觉炎症小鼠模型来 确定 FAK 抑制是否会增加 CNTF 并促进 GBC 增殖和嗅觉 神经发生。目标 4 将确定 FAK 抑制促进 OSN 轴突生长和嗅觉的能力 急性和慢性 OE 损伤后的功能恢复，结合使用遗传轴突追踪方法 与行为测试。该提案将定义 FAK 和 CNTF 的作用并验证治疗潜力 FAK抑制剂可改善损伤后的嗅觉功能。 FAK抑制剂在癌症临床中具有良好的耐受性 试验和鼻内给药避免了全身副作用。