Chronic rhinosinusitis-associated olfactory loss

描述(申请人提供)：嗅觉丧失是慢性鼻-鼻窦炎(CRS)的常见症状，显著降低受影响患者的生活质量。CRS中调节嗅觉的细胞和分子机制尚不清楚。目前的证据表明，嗅觉丧失可能是由于嗅裂受阻或炎症后嗅神经上皮功能障碍或受损所致。在CRS中，多种细胞因子通过渗入的白细胞分泌到嗅觉上皮细胞，但对这些细胞因子对外周嗅觉系统的影响知之甚少。肿瘤坏死因子-1是CRS中一种重要的细胞因子，对神经元也有多种作用。由PI产生的嗅觉上皮内可诱导的肿瘤坏死因子-1表达的小鼠模型显示，嗅觉炎症伴随着气味敏感性的丧失、嗅觉神经元的死亡和再生的抑制。在许多细胞类型中，肿瘤坏死因子-1和其他与CRS相关的细胞因子通过多个信号通路直接改变离子稳态和其他方面的细胞生理，包括激活MAP激酶和转录因子NF-B。我们的假设是CRS中存在的炎性介质通过直接作用于OSN和嗅祖细胞而导致嗅觉功能障碍。这项建议的主要目标是研究急性和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。该方案的中心假设是，细胞因子引起的炎症通过三个主要机制导致嗅觉丧失：1)嗅觉细胞对气味的脱敏；2)诱导OSN细胞凋亡；3)抑制嗅觉上皮细胞再生。将利用一种涉及小鼠遗传和分子技术的综合方法来剖析慢性嗅炎中嗅觉丧失的潜在机制。将对人类嗅觉粘膜样本进行补充研究，以确定在CRS相关性嗅觉功能障碍的发病机制中发挥作用的细胞因子，并将在小鼠模型中研究潜在的治疗药物。这项建议中描述的实验将为介导炎症介质对神经功能的影响的信号通路提供新的见解，并可能导致治疗CRS相关性嗅觉丧失的新的治疗方法。

DESCRIPTION (provided by applicant): 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-1) is a prominent cytokine in CRS that also has diverse effects on neurons. A mouse model of inducible TNF-1 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-1 and other cytokines relevant in CRS directly alter ion homeostasis and other aspects of cellular physiology through multiple signaling pathways including activation of MAP kinases and the transcription factor NF-:B. It is our hypothesis that inflammatory mediators present in CRS cause olfactory dysfunction through their direct effects on OSNs and olfactory progenitor cells. The primary goal of this proposal is to study how acute and chronic inflammation affects the function and structure of the olfactory epithelium, using our mouse model. The central hypothesis of this proposal is that inflammation induced by cytokines causes the loss of olfaction through three principal mechanisms: 1) desensitization of OSNs to odorants; 2) induction of OSN apoptosis; and 3) inhibition of olfactory epithelial regeneration. 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 the cytokines playing a role in the pathogenesis of CRS-associated olfactory dysfunction, and potential therapeutic agents will be investigated in the mouse model. The experiments described in this proposal will afford new insights into the signaling pathways that mediate inflammatory mediator effects on neural function and potentially lead to new therapeutic approaches in treating CRS- associated olfactory loss.