Chronic rhinosinusitis-associated olfactory loss

慢性鼻窦炎相关嗅觉丧失

• 批准号: 7370218
• 负责人: ANDREW P LANE
• 金额: $ 32.8万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370218
• 关键词: Ablation; Acute; Adrenal Cortex Hormones; Affect; Afferent Neurons; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biochemical; Calcium; Caspase; Cells; Cessation of life; Chronic; Cleaved cell; Condition; Cytokine Signaling; Daily; Death Domain; Dose; Doxycycline; Epithelial; Exposure to; Functional disorder; Goals; Homeostasis; Human; Inflammation; Inflammatory; Lead; Leukocytes; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; NF-kappa B; Natural regeneration; Neuroepithelial; Neurons; Neurophysiology - biologic function; Obstruction; Olfactory Epithelium; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physiological; Population; Preparation; Production; Proteins; Quality of life; Regulation; Role; Sensory; Signal Pathway; Signaling Molecule; Simulate; Smell Perception; Staining method; Stains; Stem cells; Structure; Symptoms; System; TNFRSF1A gene; TNFRSF1B gene; Techniques; Thinking; Transgenic Mice; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; cell type; cytokine; desensitization; human disease; improved; information gathering; insight; interest; mouse model; neuroepithelium; neurogenesis; neuron apoptosis; neuron loss; novel; novel therapeutics; olfactory bulb; progenitor; research study; response; rhinosinusitis; tool; transcription factor

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，显著降低患者的生活质量。传统上，嗅觉丧失被认为是由嗅觉间隙阻塞或炎症引起的嗅觉神经上皮损伤引起的。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的一个标志性特征是浸润白细胞产生的炎症细胞因子介质的存在。在这些细胞因子中，肿瘤坏死因子α (TNF-1)特别有趣，因为它在CRS相关炎症中起核心作用，并在调节神经发生和模式神经元细胞死亡方面具有公认的功能。PI最近建立了一个嗅上皮内特异性诱导TNF-1表达的小鼠模型。在该模型中，TNF-1诱导导致嗅觉敏感性丧失，并在某些条件下导致嗅觉感觉神经元（OSNs）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激活MAP激酶和转录因子NF-:B等多种信号通路直接改变钙稳态。我们的假设是，CRS中存在的炎症介质通过直接作用于osn和嗅觉祖细胞而导致嗅觉功能障碍。我们建立的小鼠诱导嗅觉炎症模型为研究急性和慢性炎症对嗅觉上皮功能和结构的影响提供了一种新的工具。该建议的中心假设是，由TNF-1诱导的炎症通过三个主要机制促进嗅觉丧失：1)osn对气味剂的脱敏；2)诱导OSN细胞凋亡；3)嗅觉上皮再生抑制。综合的方法包括生理和分子技术将被用来剖析慢性嗅觉炎症嗅觉丧失的潜在机制。本文所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，并可能为治疗crs相关嗅觉丧失提供新的治疗方法。