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Inflammation-Associated Olfactory Dysfunction: Mechanisms and Therapy

炎症相关的嗅觉功能障碍：机制和治疗

基本信息

批准号：
10063819
负责人：
ANDREW P LANE
金额：
$ 47.14万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063819
关键词：
Ablation Affect Allergic Anosmia Apoptosis Basal Cell Biological Assay Calcium Cell Death Cell Differentiation process Cell Proliferation Cell Survival Cells Cessation of life Chronic Chronic Sinusitis Clinical Trials Cytokine Signaling Dose Equilibrium Exposure to Failure Functional disorder Genetic Models Goals Histopathology Homeostasis Human Immunohistochemistry Inflammation Inflammation Mediators Inflammatory JNK-activating protein kinase Lead Leukocytes MAPK8 gene MAPK9 gene Mediating Mediator of activation protein Mitogen-Activated Protein Kinases Modeling Molecular Mus NF-kappa B Natural regeneration Neuronal Dysfunction Neuronal Injury Neurons Neurophysiology - biologic function Nose Obstruction Olfactory Epithelium Olfactory Mucosa Olfactory Pathways Olfactory dysfunction Papain Pathogenesis Pathway interactions Patients Pattern Peptides Peripheral Permeability Pharmacology Physiological Play Prevention Quality of life Recovery Role SP600125 Sampling Signal Pathway Signaling Molecule Sinusitis Smell Perception Structure TNF gene Techniques Testing Therapeutic Therapeutic Agents Time Tissue Sample Tissues Topical application Translations cell type chronic rhinosinusitis common symptom conditional knockout cytokine effective therapy experimental study functional loss human tissue improved inhibitor/antagonist insight mouse genetics mouse model nerve stem cell neuroepithelium neurogenesis neuron apoptosis neuron loss neuronal patterning novel novel therapeutic intervention novel therapeutics olfactory sensory neurons preservation response stem cells targeted treatment transcription factor

项目摘要

Project Summary The loss of the sense of smell is a common symptom of chronic rhinosinusitis (CRS) that markedly diminishes the quality of life of affected patients. The cellular and molecular mechanisms that modulate olfaction in CRS remain unknown. Current evidence suggests that olfactory loss may occur by obstruction of the olfactory cleft or by dysfunction or damage of the olfactory neuroepithelium subsequent to inflammation. In CRS, a variety of cytokine mediators are secreted into the olfactory epithelium by infiltrating leukocytes, but very little is understood about the effect of these cytokines on the peripheral olfactory system. Tumor necrosis factor alpha (TNF-) is a prominent cytokine in CRS that also has diverse effects on neurons. A mouse model of inducible TNF- expression within the olfactory epithelium generated by the PI demonstrates olfactory inflammation with loss of odorant sensitivity, death of olfactory neurons, and suppression of regeneration. In many cell types, TNF- and other cytokines relevant in CRS activate multiple signaling pathways including the MAP kinase JNK and the transcription factor NF-B. It is our hypothesis that inflammatory mediators present in CRS cause olfactory dysfunction through direct effects on OSNs and olfactory progenitor cells mediated by these pathways. The primary goal of this proposal is to study how chronic inflammation affects the function and structure of the olfactory epithelium, using our mouse model. The central hypothesis of this proposal is that the balance of activation of JNK and NF-B in OSNs leads to initial functional loss and eventual cell death. In progenitor cells, we hypothesize that cytokines, also acting through NF-B and JNK, disrupt proliferation and differentiation. An integrated approach involving mouse genetic and molecular techniques will be utilized to dissect the underlying mechanisms of olfactory loss in chronic olfactory inflammation. Complementary studies will be performed on human olfactory mucosal samples to identify signaling pathways playing a role in the pathogenesis of CRS- associated olfactory dysfunction. Potential therapeutic agents blocking the JNK pathway will be investigated in the mouse model. The experiments described in this proposal will afford new insights into the mechanisms that mediate inflammatory mediator effects on neural function and lead directly to clinical trials of novel therapeutic approaches for treating CRS-associated olfactory loss.

项目总结