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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的这项研究的长期目标是提高我们对涉及的免疫机构的理解过敏性疾病和哮喘的发病机理。自噬是一种进化保守的，高度调节确保溶酶体依赖性胞质蛋白和细胞器。在许多条件下，自动噬的改变已被折磨人类，包括衰老，癌症，神经退行性过程和免疫复杂，因为自噬对于对病原体的先天和适应性免疫复杂产生。这个项目是由最近的动机从我们的实验室和其他人发表数据，表明自噬的废除，尤其是在树突状细胞（DC），在动物模型中诱导严重的气道高反应性（AHR）（J Allergy Clin Immunol， 2016;科学。 2017）。此外，一些研究清楚地表明，ATG5中的遗传变异是一个关键自噬中的基因与儿童哮喘显着相关。为了支持这些研究，我们的初步结果表明：a）用自噬诱导剂治疗动物模型中的AHR 对过敏原敏感，b）树突状细胞中自噬的增强可诱导IL-10，并显着上升调节PD-L2，后者又将幼稚的T细胞朝向Foxp3+调节t细胞偏振，c）通用自噬的消融，尤其是在DC中，在鼠模型中诱导抗类固醇的AHR，d）自噬从中度至重度哮喘患者获得的肺树突状细胞中严重受损。我们现在建议研究是否增强自噬，特别是在抗原呈现细胞中，改善与哮喘相关的病理，抑制不需要的肺注射，最终抑制改善肺注射和功能。为了检验这一假设，我们首先设计了几种使用组织特异性和条件敲除鼠模型在我们的实验室中建立。第二，我们打算使用新颖而强大的自噬诱导剂调节自噬，该诱导剂最近被我们的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人类的初步结果在支气管肺泡液和哮喘患者的外周血液中，并确定是否治疗自噬诱导剂可以增强免疫调节途径。对于人类研究，我们成功与UCSF肺部建立了合作，并将利用其肺活检库样品从定义明确的哮喘患者队列中获得，包括嗜中性哮喘。此外，我们已经组建了一个科学家团队，包括自噬领域的领先专家和临床主管 USC的肺部学以完成我们实验室在AHR前临床模型中的丰富经验。我们相信从这项研究中获得的结果将为重要和以前的新见解提供新颖的见解自噬在哮喘中的不认识的作用。