Chronic rhinosinusitis-associated olfactory loss

慢性鼻窦炎相关嗅觉丧失

• 批准号: 8668922
• 负责人: ANDREW P LANE
• 金额: $ 34.85万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668922
• 关键词: A Mouse; Acute; Affect; Afferent Neurons; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Axon; Basal Cell; Biochemical; Breeding; Calcium; Cell physiology; Cells; Cessation of life; Chronic; Chronic Sinusitis; Cleaved cell; Cytokine Signaling; Disease; Drug usage; Electrophysiology (science); Epithelial; Epithelium; FDA approved; Failure; Functional disorder; Goals; Histology; Histopathology; Homeostasis; Human; Inflammation; Inflammation Mediators; Inflammatory; Interferons; Interleukin-1; Ions; Knockout Mice; Label; LacZ Genes; Lead; Leukocytes; MAPK8 gene; Maps; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Genetics; Mus; NF-kappa B; Natural regeneration; Neurons; Neurophysiology - biologic function; Obstruction; Olfactory Epithelium; Olfactory Receptor Neurons; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Quality of life; Recovery; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Sinusitis; Smell Perception; Staging; Stem cells; Structure; Structure of respiratory epithelium; Symptoms; System; TNF gene; Techniques; Testing; Therapeutic Agents; Tissues; Transgenic Mice; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; cell type; chronic rhinosinusitis; cytokine; desensitization; effective therapy; improved; information gathering; insight; mouse model; neuroepithelium; neurogenesis; neuron apoptosis; neuron loss; novel; novel therapeutic intervention; olfactory receptor; regenerative; research study; respiratory; transcription factor; tumor necrosis factor receptor 1A

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. The cellular and molecular mechanisms that modulate olfaction in CRS remain unknown. Current evidence suggests that olfactory loss may occur by obstruction of the olfactory cleft or by dysfunction or damage of the olfactory neuroepithelium subsequent to inflammation. In CRS, a variety of cytokine mediators are secreted into the olfactory epithelium by infiltrating leukocytes, but very little is understood about the effect of these cytokines on the peripheral olfactory system. Tumor necrosis factor alpha (TNF-1) is a prominent cytokine in CRS that also has diverse effects on neurons. A mouse model of inducible TNF-1 expression within the olfactory epithelium generated by the PI demonstrates olfactory inflammation with loss of odorant sensitivity, death of olfactory neurons, and suppression of regeneration. In many cell types, TNF-1 and other cytokines relevant in CRS directly alter ion homeostasis and other aspects of cellular physiology 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. The primary goal of this proposal is to study how acute and chronic inflammation affects the function and structure of the olfactory epithelium, using our mouse model. The central hypothesis of this proposal is that inflammation induced by cytokines causes 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 mouse genetic and molecular techniques will be utilized to dissect the underlying mechanisms of olfactory loss in chronic olfactory inflammation. Complementary studies will be performed on human olfactory mucosal samples to identify the cytokines playing a role in the pathogenesis of CRS-associated olfactory dysfunction, and potential therapeutic agents will be investigated in the mouse model. The experiments described in this proposal will afford new insights into the signaling pathways that mediate inflammatory mediator 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，显著降低了受影响患者的生活质量。调节CRS嗅觉的细胞和分子机制仍不清楚。目前的证据表明，嗅觉丧失可能发生阻塞的嗅裂或功能障碍或损伤的嗅觉神经上皮炎症。在CRS中，多种细胞因子介质通过浸润的白细胞分泌到嗅上皮中，但关于这些细胞因子对外周嗅觉系统的影响知之甚少。肿瘤坏死因子α（TNF-1）是CRS中的一种重要细胞因子，对神经元也有不同的影响。由PI产生的嗅上皮内的诱导性TNF-1表达的小鼠模型证明嗅觉炎症伴随气味敏感性丧失、嗅觉神经元死亡和再生抑制。在许多细胞类型中，CRS中相关的TNF-1和其它细胞因子通过多种信号传导途径（包括MAP激酶和转录因子NF-：B的活化）直接改变离子稳态和细胞生理学的其它方面。我们假设CRS中存在的炎症介质通过直接作用于OSN和嗅觉祖细胞而引起嗅觉功能障碍。本提案的主要目标是研究急性和慢性炎症如何影响嗅觉上皮的功能和结构，使用我们的小鼠模型。该提议的中心假设是由细胞因子诱导的炎症通过三种主要机制引起嗅觉丧失：1）OSN对气味剂的脱敏; 2）诱导OSN凋亡;和3）抑制嗅觉上皮再生。一个综合的方法，涉及小鼠遗传和分子技术将被用来解剖慢性嗅觉炎症嗅觉损失的潜在机制。将对人类嗅觉粘膜样本进行补充研究，以确定在CRS相关嗅觉功能障碍的发病机制中发挥作用的细胞因子，并将在小鼠模型中研究潜在的治疗药物。本提案中描述的实验将为介导炎症介质对神经功能的影响的信号传导途径提供新的见解，并可能导致治疗CRS相关嗅觉丧失的新治疗方法。