Study the link of autophagy dysfunction to allergic and neutrophilic asthma onset

研究自噬功能障碍与过敏性和中性粒细胞性哮喘发病的联系

• 批准号: 10408721
• 负责人: OMID AKBARI
• 金额: $ 73.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408721
• 关键词: Ablation; Affect; Aging; Allergens; Allergic; Allergic Disease; Allergic inflammation; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Asthma; Autophagocytosis; Biopsy; Bronchoalveolar Lavage Fluid; CD11c Antigens; Cell physiology; Cell surface; Cells; Childhood Asthma; Chronic; Chronic lung disease; Clinical; Clinical Data; Clinical Trials; Collaborations; Complement; Data; Dendritic Cells; Development; Disease; Effector Cell; Ensure; Extrinsic asthma; FOXP3 gene; Functional disorder; Generations; Genes; Genetic; Goals; Human; Hypersensitivity; ITGAX gene; Immune; Immune response; Impairment; In Vitro; Inflammation; Interleukin-1; Interleukin-10; Laboratories; Lead; Left; Leukocytes; Light; Link; Liquid substance; Lung; Lung diseases; Lysosomes; Malignant Neoplasms; Measures; Modeling; Mus; Nerve Degeneration; Organelles; Organism; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Play; Population; Pre-Clinical Model; Process; Production; Proteins; Protocols documentation; Publications; Publishing; Pulmonary Inflammation; Pulmonology; Pyroglyphidae; Regulatory Pathway; Regulatory T-Lymphocyte; Resolution; Role; Sampling; Science; Scientist; Severities; Steroid Resistance; System; T-Lymphocyte; Technology; Testing; Therapeutic Effect; Therapeutic Uses; Time; Tissues; Transgenic Organisms; Translating; adaptive immune response; airway hyperresponsiveness; asthmatic patient; base; clinically translatable; cohort; conditional knockout; cytokine; design; effective therapy; experience; experimental study; genetic manipulation; genetic variant; genome wide association study; improved; insight; model design; mouse model; neutrophil; new technology; novel; novel strategies; pathogen; peripheral blood; pre-clinical; pulmonary function; repository; single-cell RNA sequencing; transcription factor; translational approach

Abstract The long-term goal of this study is to increase our understanding of the immune mechanisms involved in the pathogenesis of allergic diseases and asthma. Autophagy is an evolutionarily conserved and highly regulated essential homeostatic process that ensures lysosome-dependent bulk degradation of cytosolic proteins and organelles. Alterations in autophagy have been implicated in numerous conditions afflicting humans, including aging, cancer, neurodegenerative processes, and immune responses, as autophagy is essential for the generation of both innate and adaptive immune responses to pathogens. This project is motivated by recent published data from our laboratory and others, demonstrating that abrogation of autophagy, particularly in dendritic cells (DCs), induces severe airway hyperreactivity (AHR) in animal models (J Allergy Clin Immunol, 2016; Science. 2017). Moreover, several studies clearly demonstrate that genetic variants in Atg5, a critical gene in autophagy, are significantly associated with childhood asthma. In support of those studies, our preliminary results suggest that: A) treatment with autophagy inducers reduces AHR in animal models sensitized with allergens, B) enhancement of autophagy in dendritic cells induces IL-10 and significantly up- regulates PD-L2, which in turn robustly polarizes naïve T cells towards Foxp3+ regulatory T cells, C) genetic ablation of autophagy, particularly in DCs, induces steroid-resistant AHR in murine models, and D) autophagy is severely impaired in pulmonary dendritic cells obtained from patients with moderate to severe asthma. We now propose to investigate if enhancement of autophagy, particularly among antigen presenting cells, ameliorates pathology associated with asthma, suppresses unwanted lung inflammation and ultimately improves lung inflammation and function. To test this hypothesis, we first designed several approaches utilizing tissue-specific and conditional knockout murine models established in our laboratory. Second, we intend to modulate autophagy using a novel and robust autophagy inducer that was discovered recently by our collaborators at USC. Finally, we will extend our preliminary results in humans by assessing autophagy levels in the bronchoalveolar fluid and peripheral blood of patients with asthma, and determine if treatment with autophagy inducers can enhance immune-regulatory pathways. For the human studies we successfully established collaborations with UCSF pulmonary group and will utilized their lung biopsy repository samples obtained from well-defined cohorts of patients with asthma including neutrophilic asthma. Furthermore, we have assembled a team of scientists including a leading expert in autophagy and the chief of clinical pulmonology at USC to complement our laboratory's extensive experience in pre-clinical models of AHR. We believe that the results obtained from this study will provide novel insights into an important and previously unrecognized role of autophagy in asthma.

摘要 这项研究的长期目标是增加我们对涉及到的免疫机制的了解 过敏性疾病和哮喘的发病机制。自噬是一种进化上保守且高度调控的 基本的动态平衡过程，确保溶酶体依赖的胞浆蛋白和 细胞器。自噬的改变与许多折磨人类的疾病有关，包括 衰老、癌症、神经退化过程和免疫反应，因为自噬对 对病原体产生先天和获得性免疫反应。这个项目的动机是最近 我们实验室和其他实验室公布的数据表明，废除自噬，特别是在 树突状细胞(DC)，在动物模型中诱导严重的呼吸道高反应(AHR)(J过敏性Clin免疫， 2016年；科学。2017年)。此外，几项研究清楚地表明，ATG5中的遗传变异是一种关键的 自噬基因与儿童哮喘显著相关。为支持这些研究，我们的 初步结果表明：a)用自噬诱导剂治疗可降低动物模型中的AHR 过敏原致敏，B)树突状细胞自噬增强诱导IL-10，并显著上调- 调节PD-L2，从而使幼稚的T细胞强烈地极化为Foxp3+调节性T细胞，C)遗传 自噬的消融，特别是在DC中，在小鼠模型中诱导类固醇耐药的AHR，以及D)自噬 从中到重度哮喘患者获得的肺树突状细胞严重受损。我们 现在建议研究是否增强自噬，特别是在抗原提呈细胞之间， 改善与哮喘相关的病理，抑制不必要的肺部炎症，最终 改善肺部炎症和功能。为了验证这一假设，我们首先设计了几种方法 本实验室建立的组织特异性和条件性基因敲除小鼠模型。第二，我们打算 使用我们最近发现的一种新颖而强大的自噬诱导剂来调节自噬 南加州大学的合作者。最后，我们将通过评估自噬水平来扩展我们在人类身上的初步结果 在哮喘患者的支气管肺泡液和外周血中，并确定治疗是否 自噬诱导剂可以增强免疫调节途径。对于人体研究，我们成功地 与加州大学旧金山分校肺科小组建立了合作关系，并将利用他们的肺活检库样本 从明确界定的哮喘患者队列中获得，包括中性粒细胞哮喘。此外，我们 已经组建了一个科学家团队，其中包括一位自噬方面的顶尖专家和临床科主任 以补充我们实验室在AHR临床前模型方面的丰富经验。我们 相信从这项研究中获得的结果将为一个重要的和以前的 自噬在哮喘中未被认识到的作用。