Friday, November 22, 2024
11/22/2024
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.
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