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。传统上，嗅觉丧失被认为是由于嗅裂受阻或炎症后嗅神经上皮受损所致。虽然这在某些情况下是正确的，但很可能还有其他细胞和分子机制调节CRS的嗅觉功能。CRS的一个显著特征是存在由渗透的白细胞产生的炎性细胞因子介质。在这些细胞因子中，肿瘤坏死因子α(TNF-1)尤其令人感兴趣，因为它在CRS相关炎症中发挥核心作用，并且在调节神经发生和模式神经细胞死亡方面具有公认的功能。PI最近建立了一个可诱导的肿瘤坏死因子-1表达的小鼠模型，该模型专门在嗅觉上皮细胞中表达。在这个模型中，诱导肿瘤坏死因子-1会导致嗅觉敏感度的丧失，并在一定条件下导致嗅觉感觉神经元(OSN)死亡。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种信号通路直接改变钙稳态，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。我们建立的诱导性嗅炎小鼠模型为研究急性和慢性炎症对嗅上皮功能和结构的影响提供了一种新的工具。该方案的中心假设是，由肿瘤坏死因子-1诱导的炎症通过三个主要机制促进嗅觉丧失：1)嗅觉细胞对气味的脱敏；2)诱导嗅觉细胞凋亡；3)抑制嗅觉上皮再生。综合运用生理学和分子生物学技术，我们将剖析慢性嗅炎中嗅觉丧失的潜在机制。这项建议中描述的实验将为介导炎性细胞因子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. Traditionally, olfactory loss has been thought to occur by obstruction of the olfactory cleft or damage to the olfactory neuroepithelium subsequent to inflammation. While this is true in some cases, it is likely that there are other cellular and molecular mechanisms that modulate olfactory function in CRS. A hallmark feature of CRS is the presence of inflammatory cytokine mediators produced by infiltrating leukocytes. Among these cytokines, tumor necrosis factor alpha (TNF-1) is particularly interesting because of its central role in CRS- associated inflammation and its recognized functions in regulating neurogenesis and patterned neuronal cell death. The PI has recently generated a mouse model of inducible TNF-1 expression specifically within the olfactory epithelium. TNF-1 induction in this model causes loss of odorant sensitivity and, under certain conditions, death of olfactory sensory neurons (OSNs). In many cell types, TNF-1 and other cytokines relevant in CRS directly alter calcium homeostasis 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. Our induced olfactory inflammation mouse model provides a novel tool with which to study the effect of acute and chronic inflammation on the function and structure of the olfactory epithelium. The central hypothesis of this proposal is that inflammation induced by TNF-1 promotes 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 physiological and molecular techniques will be utilized to dissect the underlying mechanisms of olfactory loss in chronic olfactory inflammation. The experiments described in this proposal will afford new insights into the signaling pathways that mediate inflammatory cytokine effects on neural function and potentially lead to new therapeutic approaches in treating CRS-associated olfactory loss.