Inflammation-Associated Olfactory Dysfunction: Mechanisms and Therapy

项目摘要 嗅觉丧失是慢性鼻-鼻窦炎(CRS)的常见症状，明显 降低了受影响患者的生活质量。细胞和分子机制 CRS对嗅觉的调节尚不清楚。目前的证据表明，可能会发生嗅觉丧失。 因嗅裂受阻或嗅神经上皮功能障碍或损伤 在发炎之后。在CRS中，各种细胞因子介质被分泌到嗅觉。 但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-是CRS中的重要细胞因子 这对神经元也有不同的影响。一种可诱导肿瘤坏死因子-表达的小鼠模型 PI产生的嗅觉上皮显示嗅觉发炎并失去气味 敏感度，嗅觉神经元死亡，以及再生抑制。在许多细胞类型中，肿瘤坏死因子- 与CRS相关的其他细胞因子激活包括MAP激酶在内的多个信号通路 JNK和转录因子NF-B。我们的假设是，炎症介质存在于 CRS通过直接作用于OSNs和嗅祖细胞导致嗅觉功能障碍 通过这些途径进行调节。这项提议的主要目标是研究慢性炎症如何 利用我们的小鼠模型，影响嗅觉上皮的功能和结构。中环 这一假设认为，在OSN中，JNK和NF-B的激活平衡导致了最初的 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 通过核因子-B和JNK，干扰细胞的增殖和分化。一种集成的方法，涉及 将利用小鼠遗传和分子技术来剖析其潜在机制。 慢性嗅炎中的嗅觉丧失。将对人类进行补充性研究 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 相关的嗅觉功能障碍。阻断JNK途径的潜在治疗药物将是 在小鼠模型中进行了研究。这项提案中描述的实验将提供新的见解 探讨炎症介质直接影响神经功能的机制 治疗CRS相关性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.