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：
10653187
负责人：
OMID AKBARI
金额：
$ 73.16万
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/10653187
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 Disease Clinical 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 Innate Immune Response Interleukin-1 Interleukin-10 Laboratories 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 Mice Translating adaptive immune response airway hyperresponsiveness asthmatic patient clinical translation cohort conditional knockout cytokine design effective therapy experience experimental study genetic manipulation genetic variant genome wide association study improved insight 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增加我们对参与免疫机制的了解过敏性疾病和哮喘的发病机制在进化上是保守且高度调控的。确保溶酶体依赖性胞质蛋白大量降解的重要稳态过程自噬的改变与人类的许多疾病有关，包括衰老、癌症、神经退行性过程和免疫反应，因为自噬对于该项目的动机是对病原体产生先天性和适应性免疫反应。我们实验室和其他实验室发表的数据表明，自噬的废除，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）（J Allergy Clin Nutrition， 2016 年；《科学》2017 年）。自噬基因与儿童哮喘显着相关，我们的研究支持这些研究。初步结果表明：A) 使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 并显着上调调节 PD-L2，进而将幼稚 T 细胞强力极化为 Foxp3+ 调节性 T 细胞，C) 遗传自噬的消除，特别是在 DC 中，在小鼠模型中诱导类固醇抗性 AHR，以及 D) 自噬从中度至重度哮喘患者中获得的肺树突状细胞严重受损。现在建议研究自噬是否增强，特别是在抗原呈递细胞中，改善与哮喘相关的病理，抑制不必要的肺部炎症，并最终为了检验这一假设，我们首先设计了几种利用的方法。其次，我们打算在我们的实验室建立组织特异性和条件性敲除小鼠模型。使用我们最近发现的一种新颖且强大的自噬诱导剂来调节自噬最后，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。检测哮喘患者的支气管肺泡液和外周血，并确定是否采用自噬诱导剂可以增强免疫调节途径，我们成功地进行了人类研究。与加州大学旧金山分校肺科小组建立合作，并将利用其肺活检储存库样本从明确定义的哮喘患者（包括中性粒细胞性哮喘）队列中获得。组建了一个科学家团队，其中包括自噬领域的顶尖专家和临床首席科学家南加州大学的肺病学实验室补充了我们实验室在 AHR 临床前模型方面的丰富经验。相信从这项研究中获得的结果将为以前的重要研究提供新的见解自噬在哮喘中的作用尚未被认识。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinct Roles of LFA-1 and ICAM-1 on ILC2s Control Lung Infiltration, Effector Functions, and Development of Airway Hyperreactivity.

LFA-1 和 ICAM-1 对 ILC2 控制肺部浸润、效应器功能和气道高反应性发展的独特作用。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Hurrell, Benjamin P;Howard, Emily;Galle;Helou, Doumet Georges;Shafiei;Painter, Jacob D;Akbari, Omid
通讯作者：
Akbari, Omid

Absence of CD28-CTLA4-PD-L1 Costimulatory Molecules Reduces Herpes Simplex Virus 1 Reactivation.

CD28-CTLA4-PD-L1 共刺激分子的缺失可减少单纯疱疹病毒 1 的重新激活。

DOI：
发表时间：
2021
期刊：
影响因子：
6.4
作者：
Matundan, Harry H;Jaggi, Ujjaldeep;Yu, Jack;Akbari, Omid;Ghiasi, Homayon
通讯作者：
Ghiasi, Homayon

Creation of a Single Cell RNASeq Meta-Atlas to Define Human Liver Immune Homeostasis.

创建单细胞 RNASeq 元图谱来定义人类肝脏免疫稳态。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Rocque, Brittany;Barbetta, Arianna;Singh, Pranay;Goldbeck, Cameron;Helou, Doumet Georges;Loh, Yong;Ung, Nolan;Lee, Jerry;Akbari, Omid;Emamaullee, Juliet
通讯作者：
Emamaullee, Juliet

Unique immune and inflammatory cytokine profiles may define long COVID syndrome.

独特的免疫和炎症细胞因子谱可能定义长期新冠肺炎综合征。

DOI：
发表时间：
2023-10
期刊：
影响因子：
4.6
作者：
Allan;Akbari, Omid;Kojima, Noah;Saavedra, Edwyn;Chellamuthu, Prithivi;Denny, Nicholas;MacMullan, Melanie A;Hess, Victoria;Shacreaw, Maria;Brobeck, Matthew;Turner, Frederick;Slepnev, Vladimir I;Ibrayeva, Albina;Klausner, Jeffrey
通讯作者：
Klausner, Jeffrey

Enhancing autophagy in CD11c+ antigen-presenting cells as a therapeutic strategy for acute respiratory distress syndrome.

增强 CD11c 抗原呈递细胞的自噬作为急性呼吸窘迫综合征的治疗策略。

DOI：
发表时间：
2023-08-29
期刊：
影响因子：
8.8
作者：
Quach, Christine;Helou, Doumet Georges;Li, Meng;Hurrell, Benjamin Pierre;Howard, Emily;Shafiei;Soroosh, Pejman;Ou, Jing;Razani, Babak;Rehan, Virender;Akbari, Omid
通讯作者：
Akbari, Omid