The Mechanism of Inflammation-mediated Olfactory Dysfunction in Chronic Rhinosinusitis

慢性鼻窦炎炎症介导的嗅觉障碍的机制

基本信息

批准号：
9313233
负责人：
Justin H Turner
金额：
$ 15.8万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313233
关键词：
Adrenal Cortex Hormones Affect Anatomy Animal Model Animals Apoptosis Biopsy Specimen Cell Death Cell Differentiation process Cell Proliferation Cell physiology Cells Chronic Clinical Databases Differentiation and Growth Disease Epithelial Functional disorder Goals Human Individual Inflammation Inflammatory Interferon Type II Interferons Interleukin-1 Interleukin-1 beta Interleukin-17 Interleukin-6 Measures Mediating Natural regeneration Nerve Regeneration Neurons Obstruction Olfactory Epithelium Operative Surgical Procedures Oral Pathway interactions Patients Play Polyps Process Quality of life Reporting Role Severity of illness Sinus Smell Perception Symptoms System TNF gene Testing Tissue Procurements Tissues Transgenic Mice cell motility chronic rhinosinusitis common symptom cytokine cytotoxic functional loss insight mouse model nerve stem cell neurogenesis neuron loss neurotoxic overexpression patient safety prospective public health relevance receptor regenerative repository rhinosinusitis therapeutic target

项目摘要

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.

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有重大影响 CRS 中观察到的嗅觉丧失背后的病理生理学尚不清楚，但是。动物模型表明，慢性炎症是慢性鼻窦炎的标志，可能会导致成熟或功能性嗅觉神经元的丧失，而嗅觉神经元再生的抑制会导致慢性鼻窦炎。炎症细胞的流入和多种促炎细胞因子水平的升高，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的潜力。和神经发生过程，这两者都会导致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是通过以下组合介导的：1) 对神经元细胞迁移或分化的影响，2) 抑制。神经祖细胞增殖，或 3) 诱导神经祖细胞死亡或凋亡该提议的中心假设是神经毒性促炎细胞因子在 CRS 中过度表达，并且细胞因子表达和功能的改变导致 CRS 相关炎症和嗅觉。我们将使用人类嗅觉组织来测试这一假设，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影响的机制研究。目标 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。目标 2 将确定促炎细胞因子的受体是否在人类嗅觉神经元和神经元祖细胞上表达，并将评估我们捕获了促炎细胞因子通过嗅觉神经元和神经祖细胞上表达的同源受体发挥作用。负调节嗅觉神经元存活和再生的研究结果将深入了解 CRS 中观察到的嗅觉功能障碍的机制，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。