Inflammation-Associated Olfactory Dysfunction: Mechanisms and Therapy

项目摘要 嗅觉丧失是慢性鼻窦炎（CRS）的常见症状， 降低了患者的生活质量。细胞和分子机制， 调节CRS中的嗅觉仍然是未知的。目前的证据表明，嗅觉丧失可能会发生 通过嗅裂阻塞或通过嗅觉神经上皮的功能障碍或损伤 炎症后。在CRS中，多种细胞因子介质分泌到嗅觉中， 上皮细胞浸润的白细胞，但很少了解这些细胞因子的作用， 外围嗅觉系统肿瘤坏死因子α（TNF-α）是CRS中的主要细胞因子 对神经元也有不同的影响。诱导型TNF-α表达的小鼠模型 由PI产生的嗅上皮显示嗅觉炎症伴气味丧失 敏感性，嗅觉神经元死亡和再生抑制。在许多细胞类型中，TNF-α CRS相关的细胞因子激活多种信号通路，包括MAP激酶 JNK和转录因子NF-κ B B。我们假设炎症介质存在于 CRS通过直接作用于OSN和嗅觉祖细胞引起嗅觉功能障碍 通过这些途径。这项提案的主要目标是研究慢性炎症如何 影响嗅觉上皮的功能和结构，使用我们的小鼠模型。中央 这一建议的假设是，OSN中JNK和NF-κ B B活化的平衡导致了OSN的初始活化。 功能丧失和最终的细胞死亡。在祖细胞中，我们假设细胞因子也起作用， 通过NF-κ B B和JNK破坏增殖和分化。一种综合办法， 小鼠遗传和分子技术将被用来解剖的潜在机制， 慢性嗅觉炎症的嗅觉丧失。将对人类进行补充研究 嗅觉粘膜样本，以确定在CRS发病机制中发挥作用的信号通路- 相关的嗅觉障碍。阻断JNK通路的潜在治疗剂将是 在小鼠模型中进行了研究。该提案中描述的实验将提供新的见解 介导炎症介质对神经功能的影响并直接导致 用于治疗CRS相关嗅觉丧失的新治疗方法的临床试验。

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.