Chronic rhinosinusitis-associated olfactory loss

慢性鼻窦炎相关嗅觉丧失

基本信息

批准号：
7755020
负责人：
ANDREW P LANE
金额：
$ 32.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2011-07-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7755020
关键词：
Acute Address Affect Afferent Neurons Animals Area Basic Science Calcium Cessation of life Chronic Cleaved cell Clinical Critiques Data Environment Epithelial Epithelium Foundations Functional disorder Histologic Homeostasis Human Inflammation Inflammation Mediators Inflammatory Lead Left Leukocytes Mediating Mediator of activation protein Medical Mitogen-Activated Protein Kinases Modeling Molecular Morphology Mosaicism Mus Natural regeneration Nature Neurophysiology - biologic function Obstruction Olfactory Epithelium Operative Surgical Procedures Patients Pattern Physiological Principal Investigator Process Quality of life Role Scientist Signal Pathway Smell Perception Stem cells Structure Symptoms System Techniques Therapeutic Translational Research Tumor Necrosis Factor-alpha cell type chronic rhinosinusitis cytokine desensitization human disease innovation insight interest mouse model neuroepithelium neurogenesis neuron apoptosis neuron loss novel novel therapeutic intervention programs research study response tool transcription factor

项目摘要

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.

描述（由申请人提供）：嗅觉丧失是慢性鼻窦炎（CRS）的常见症状，显着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炎症引起的嗅觉裂隙阻塞或嗅神经上皮损伤造成的。虽然在某些情况下确实如此，但很可能存在其他细胞和分子机制来调节 CRS 中的嗅觉功能。 CRS 的一个标志性特征是存在由浸润白细胞产生的炎症细胞因子介质。在这些细胞因子中，肿瘤坏死因子 α (TNF-1) 特别令人感兴趣，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性神经元细胞死亡方面具有公认的功能。 PI 最近创建了一种可诱导 TNF-1 表达的小鼠模型，特别是在嗅觉上皮内。该模型中的 TNF-1 诱导会导致气味敏感性丧失，并在某些条件下导致嗅觉感觉神经元 (OSN) 死亡。在许多细胞类型中，TNF-1 和其他与 CRS 相关的细胞因子通过多种信号通路（包括 MAP 激酶和转录因子 NF-:B 的激活）直接改变钙稳态。我们的假设是，CRS 中存在的炎症介质通过直接影响 OSN 和嗅觉祖细胞而导致嗅觉功能障碍。我们诱导的嗅觉炎症小鼠模型提供了一种新的工具来研究急性和慢性炎症对嗅觉上皮功能和结构的影响。该提议的中心假设是，TNF-1 诱导的炎症通过三种主要机制促进嗅觉丧失：1）OSN 对气味剂的脱敏； 2)诱导OSN凋亡； 3)抑制嗅上皮再生。将利用涉及生理学和分子技术的综合方法来剖析慢性嗅觉炎症中嗅觉丧失的潜在机制。该提案中描述的实验将为介导炎症细胞因子对神经功能影响的信号通路提供新的见解，并可能导致治疗 CRS 相关嗅觉丧失的新治疗方法。