Space Activation for Josh Levy Lab

乔什·利维实验室的空间激活

• 批准号: 10923719
• 负责人: Joshua Levy
• 金额: $ 68.74万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10923719
• 关键词: Affect; Ageusia; Allergic; Anosmia; Arachidonic Acids; Basic Science; Biological; Biological Models; CNR2 gene; COVID-19; Chronic; Chronic Sinusitis; Clinical; Clinical Research; Communications Media; Data; Disease; Eicosanoids; Epithelium; Evaluation; Gene Expression; Human; Inflammation; Inflammatory; Modeling; Nasal Polyps; Olfaction Disorders; Olfactory Epithelium; Olfactory dysfunction; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Physiological; Research; Role; Safety; Sampling; Sinus; Smell Perception; System; Taste Disorders; Taste Perception; Treatment Efficacy; airway epithelium; aspirin-exacerbated respiratory disease; design; endogenous cannabinoid system; experimental study; improved; insight; novel; novel therapeutics; overexpression; patient population; pre-clinical; prevent; programs; respiratory; respiratory virus; rhinosinusitis; safety testing; therapy development; transcriptome sequencing; translational study

Our basic science studies are focused on the sinonasal epithelium as a model system to understand chronic inflammatory pathways that are disrupted in sinus disease and other forms of acquired smell/taste loss. We previously discovered an increased expression of the type-2 cannabinoid receptor in Aspirin-exacerbated respiratory disease (AERD), a recalcitrant form of chronic sinusitis with associated loss of smell. This year we have begun to evaluate the physiologic effects of this over-expression in epithelial models from patients with AERD, with a focus on the sinonasal epithelial barrier. Additionally, we have completed a bulk RNA-Seq experiment with comparison of epithelial gene expression among patients with AERD, allergic fungal rhinosinusitis (AFRS) and normal controls without sinus disease or other forms of olfactory dysfunction. AFRS is an equally difficult to treat form of sinus disease with associated loss of smell. Our data reveal novel insights suggesting the role of arachidonic acid and the eicosanoid system in the pathogenesis of both forms of sinus disease. Our translational studies consist of preclinical experiments aimed at developing therapies to reverse chronic epithelial inflammation in humans with loss of smell/taste. Targets of these studies include the eicosanoid and endogenous cannabinoid systems identified as being dysregulated in chronic sinus disease. Clinically we are evaluating the use of dupilumab for the treatment of AFRS and loss of smell. Dupilumab is a respiratory biologic that significantly improves the sense of smell in patients with nasal polyps. However, the efficacy of this intervention among patients with AFRS is yet to be demonstrated in phase III clinical trials. We therefore seek to establish the safety and efficacy in this patient population while collecting patient samples for further study of the mechanisms underlying the impressive impact of this drug on the sense of smell.

我们的基础科学研究集中在鼻窦上皮作为模型系统，以了解慢性炎症通路在鼻窦疾病和其他形式的获得性嗅觉/味觉丧失中被破坏。我们先前发现阿司匹林加重呼吸道疾病（AERD）中2型大麻素受体的表达增加，AERD是一种慢性鼻窦炎的非特异性形式，伴有嗅觉丧失。 今年，我们已经开始在AERD患者的上皮模型中评估这种过度表达的生理效应，重点是鼻窦上皮屏障。此外，我们还完成了大量RNA-Seq实验，比较了AERD、过敏性真菌性鼻窦炎（AFRS）患者和无鼻窦疾病或其他形式嗅觉功能障碍的正常对照组的上皮基因表达。AFRS是一种同样难以治疗的鼻窦疾病，伴有嗅觉丧失。我们的数据揭示了新的见解，表明花生四烯酸和类花生酸系统在这两种形式的鼻窦疾病的发病机制中的作用。 我们的转化研究包括临床前实验，旨在开发治疗方法，以逆转人类嗅觉/味觉丧失的慢性上皮炎症。这些研究的目标包括被确定为在慢性鼻窦疾病中失调的类二十烷酸和内源性大麻素系统。 在临床上，我们正在评估dupilumab用于治疗AFRS和嗅觉丧失的用途。Dupilumab是一种呼吸道生物制剂，可显著改善鼻息肉患者的嗅觉。然而，这种干预在AFRS患者中的疗效尚未在III期临床试验中得到证实。因此，我们寻求在该患者人群中建立安全性和有效性，同时收集患者样本，以进一步研究该药物对嗅觉产生显著影响的机制。