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: 10204106
• 负责人: OMID AKBARI
• 金额: $ 73.09万
• 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/10204106
• 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 Inflammation; 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; 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免疫机制的理解， 过敏性疾病和哮喘的发病机制。自噬是一种进化上保守和高度调控的 基本的稳态过程，确保胞浆蛋白质的溶酶体依赖性大量降解， 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，神经退行性过程和免疫反应，因为自噬对于 产生对病原体的先天性和适应性免疫应答。该项目的动机是最近 从我们的实验室和其他人发表的数据，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气道高反应性（AHR）（JAllergyClinImmunol， 2016;科学。2017年）。此外，一些研究清楚地表明，Atg 5的遗传变异，一个关键的 自噬基因与儿童哮喘有显著相关性。为了支持这些研究，我们 初步结果表明：A）在动物模型中，用自噬诱导剂治疗降低了AHR B）树突状细胞中自噬的增强诱导IL-10，并显著上调 调节PD-L2，PD-L2又使幼稚T细胞向Foxp 3+调节性T细胞强烈极化，C）遗传性 自噬的消除，特别是在DC中，在鼠模型中诱导类固醇抗性AHR，和D）自噬 在从中度至重度哮喘患者获得的肺树突状细胞中严重受损。我们 现在提出研究是否增强自噬，特别是在抗原呈递细胞中， 改善与哮喘相关的病理，抑制不需要的肺部炎症，并最终 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， 组织特异性和条件性基因敲除小鼠模型。第二，我们打算 调节自噬使用一种新的和强大的自噬诱导剂，最近发现，我们的 USC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中的初步结果。 哮喘患者的支气管肺泡液和外周血中，并确定是否用 自噬诱导剂可以增强免疫调节途径。对于人类研究，我们成功地 与加州大学旧金山分校肺部组建立了合作关系，并将利用他们的肺活检储存库样本 从明确定义的哮喘患者（包括嗜酸性哮喘）队列中获得。而且我们 已经组建了一个科学家团队，包括一位自噬领域的顶尖专家和一位临床医学博士。 在南加州大学的肺病学，以补充我们的实验室在AHR的临床前模型的丰富经验。我们 我相信，从这项研究中获得的结果将提供新的见解，一个重要的和以前的 自噬在哮喘中未被认识的作用。