The Mechanism of Inflammation-mediated Olfactory Dysfunction in Chronic Rhinosinusitis

 描述（由申请人提供）：嗅觉丧失通常发生在慢性鼻窦炎（CRS）患者中，对生活质量和患者安全性有重大影响。在CRS中观察到的嗅觉丧失背后的病理生理学尚不清楚，但动物模型表明慢性炎症（CRS的标志）可能导致成熟或功能性嗅觉神经元的丧失和嗅觉神经元再生的抑制。CRS导致炎性细胞流入和多种促炎细胞因子水平升高，包括TNF-α、IL-1β、IL-6、IL-17和IFN-γ。这些细胞因子尤其具有负调节神经元再生和神经发生过程的潜力，这两者都可以引起功能性神经元的短暂或永久丧失。这些再生途径的抑制通常通过以下的组合介导：1）对神经元细胞迁移或分化的影响，2）神经元祖细胞增殖的抑制，或3）神经元祖细胞死亡或凋亡的诱导。该提议的中心假设是神经毒性促炎细胞因子在CRS中过表达，并且细胞因子表达和功能的改变有助于CRS相关的炎症和嗅觉丧失。我们将使用人源性嗅觉组织来检验这一假设，包括直接评估促炎细胞因子对嗅觉神经元和神经元祖细胞的作用的机制研究。目的1将评估人类嗅觉组织中神经毒性细胞因子的表达，并确定细胞因子表达是否与嗅觉功能的客观测量相关。目的2将确定是否受体的促炎细胞因子表达的人类嗅觉神经元和神经元祖细胞，并将评估个别细胞因子对细胞过程，如增殖，分化和凋亡的影响。我们推测，促炎细胞因子，通过嗅觉神经元和神经元祖细胞上表达的同源受体起作用，负调节嗅觉神经元的存活和再生。这项研究的结果将为CRS中观察到的嗅觉功能障碍机制提供深入了解，并可能有助于确定选择性治疗CRS相关嗅觉丧失的特定治疗靶点。

 DESCRIPTION (provided by applicant): Loss of the sense of smell commonly occurs in patients with chronic rhinosinusitis (CRS) and has major impacts on quality of life and patient safety. The pathophysiology behind the olfactory loss observed in CRS is not clearly understood, but animal models suggest that chronic inflammation, a hallmark of CRS, may result in a loss of mature or functional olfactory neurons and an inhibition in olfactory neuron regeneration. CRS results in an influx of inflammatory cells and elevated levels of multiple pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17, and IFN-γ. These cytokines, in particular, have the potential to negatively modulate neuronal regeneration and the process of neurogenesis, both of which can cause transient or permanent loss of functional neurons. Inhibition of these regenerative pathways is typically mediated through a combination of: 1) effects on neuronal cell migration or differentiation, 2) Inhibition of neuronal progenitor cell proliferation, or 3) induction of neuronal progenitor cell death or apoptosis. The central hypothesis of this proposal is that neurotoxic pro-inflammatory cytokines are overexpressed in CRS and that alteration in cytokine expression and function contributes to CRS-related inflammation and olfactory loss. We will test this hypothesis using human-derived olfactory tissue, including mechanistic studies that directly assess the effect of pro-inflammatory cytokines on olfactory neurons and neuronal progenitor cells. Aim 1 will assess the expression of neurotoxic cytokines in human olfactory tissue and determine whether cytokine expression correlates with objective measures of olfactory function. Aim 2 will determine whether receptors for pro-inflammatory cytokines are expressed on human olfactory neurons and neuronal progenitor cells and will assess the effects of individual cytokines on cellular processes such as proliferation, differentiation, and apoptosis. We hypothesize that pro-inflammatory cytokines, acting through cognate receptors expressed on olfactory neurons and neuronal progenitor cells, negatively modulate olfactory neuron survival and regeneration. Findings from this study will provide insight into the mechanisms of olfactory dysfunction observed in CRS and may help to identify specific therapeutic targets for the selective treatment of CRS-associated olfactory loss.