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.

项目概要嗅觉丧失是慢性鼻窦炎 (CRS) 的常见症状，降低受影响患者的生活质量的细胞和分子机制。调节 CRS 中的嗅觉仍然未知。目前的证据表明可能会发生嗅觉丧失。由于嗅裂阻塞或嗅神经上皮功能障碍或损伤炎症后，多种细胞因子介质被分泌到嗅觉中。通过浸润白细胞对上皮细胞产生影响，但人们对这些细胞因子对上皮细胞的影响知之甚少。外周嗅觉系统肿瘤坏死因子α (TNF-α) 是 CRS 中的一个重要细胞因子。对神经元也有不同的影响诱导性 TNF-α 表达的小鼠模型。 PI 产生的嗅觉上皮表现出嗅觉炎症并伴有气味丧失在许多细胞类型中，TNF-α 会影响嗅觉神经元的敏感性、死亡和再生抑制。和其他与 CRS 相关的细胞因子激活多种信号通路，包括 MAP 激酶我们假设炎症介质存在于 JNK 和转录因子 NF-κB 中。 CRS 通过直接影响 OSN 和嗅觉祖细胞导致嗅觉功能障碍该提案的主要目标是研究慢性炎症如何介导。使用我们的小鼠模型影响嗅觉上皮的功能和结构。该提案的假设是 OSN 中 JNK 和 NF-κB 的激活平衡导致初始在祖细胞中，我们欺负细胞因子，也发挥作用。通过 NF-κB 和 JNK，破坏增殖和分化的综合方法。将利用小鼠遗传和分子技术来剖析其潜在机制慢性嗅觉炎症中的嗅觉丧失将在人类身上进行。嗅粘膜样本以确定在 CRS 发病机制中发挥作用的信号通路阻断 JNK 通路的潜在治疗药物将是相关的嗅觉功能障碍。本提案中描述的实验将提供新的见解。研究介导炎症介质对神经功能的影响并直接导致治疗 CRS 相关嗅觉丧失的新治疗方法的临床试验。