Viral and allergen-driven immunity in chronic lung disease

慢性肺病中病毒和过敏原驱动的免疫

基本信息

批准号：
9886480
负责人：
Nicholas W Lukacs
金额：
$ 68.49万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-03-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886480
关键词：
Address Airway Disease Allergens Allergic Area Asthma Autophagocytosis Biological Response Modifiers Cell physiology Cells Cellular Metabolic Process Chronic Chronic Disease Chronic lung disease Clinical Development Disease Environment Functional disorder Goals Grant Immune Immune response Immunity Inflammation Investigation Knowledge Laboratories Link Lung Lung diseases Lymphocyte Metabolic Control Metabolism Mononuclear National Heart, Lung, and Blood Institute Nature Neonatal Phenotype Population Process Research Respiratory physiology Role Severity of illness Shapes Stem Cell Factor Steroid Resistance Structure Therapeutic Intervention Training Viral Viral Respiratory Tract Infection Work asthmatic chemokine cytokine eosinophil epigenetic regulation immune activation immunoregulation insight lung development lung repair mucus hypersecretion notch protein novel novel therapeutics response targeted treatment therapeutic target

项目摘要

Abstract Severe allergic asthmatic disease is characterized by significant airway structure changes and chronic inflammation predominated by eosinophils, mononuclear cells, and lymphocytes, and accompanied by mucus hypersecretion that depends upon the nature of the immune response. The most severe airways disease progresses through a continuum of responses ranging from manageable airway dysfunction to a steroid resistant state that is often a result of a severe exacerbation that is difficult to control. Over the more than 25 years of work in this area my laboratory has defined the role of numerous cytokines and chemokines that initiate and drive the pulmonary immune responses, identified innate immune molecules that shape the immune phenotype (TLRs, Notch), defined a role for respiratory viral infections that induce and exacerbate disease, examined epigenetic regulation of immune cell function, and more recently identified metabolic control of innate immune cell activation. Many of our previous discoveries have revealed potential therapeutic targets for pulmonary diseases, including studies in our 2nd NHLBI RO1 that examine stem cell factor and ILC2. One of our present NHLBI RO1 grants is examining the role of autophagy and cellular metabolism for innate immune cell function. Our most recent studies are addressing additional mechanisms linked to trained immunity within the lung, as well as development of lung responses that alter the structural and functional integrity of the lung. While we will be combining 2 RO1 with divergent themes, our overall objective of understanding how the pulmonary immune environment is developed and maintained during disease is central to all of our studies. Together, our past and ongoing investigations are revealing an integrated understanding of not only the immune responses during disease development, but also the long-term consequence of early disease and its relationship to altered lung function and development. Using this R35 mechanism, we will continue expanding on these areas of research that will be paradigm shifting. We will focus on specific goals including 1) determine how early RSV-induced responses in the lung alter the innate immune cell phenotype and induce lung structural changes that predisposes the lung to later allergic/asthmatic responses; 2) examine the role that stem cell factor (SCF) has on altering the activation of ILC2 populations in chronic pulmonary disease; and 3) investigate how cell metabolism alters immune cell development during disease to maintain and extend disease severity. Completion of these studies will provide new insights, establish new paradigms, and complete proof of concept studies needed to advance knowledge and validate new, therapeutically relevant mechanisms in clinical disease.

抽象的严重过敏性哮喘疾病的特点是显着的气道结构改变和慢性以嗜酸性粒细胞、单核细胞和淋巴细胞为主，伴有粘液的炎症分泌过多取决于免疫反应的性质。最严重的气道疾病通过一系列反应进行进展，从可控制的气道功能障碍到类固醇耐药状态通常是难以控制的严重恶化的结果。超过25以上我的实验室在这一领域多年的工作已经确定了许多细胞因子和趋化因子的作用启动并驱动肺部免疫反应，确定了塑造肺部免疫反应的先天免疫分子免疫表型（TLR，Notch），定义了诱导和加剧呼吸道病毒感染的作用疾病，检查了免疫细胞功能的表观遗传调控，以及最近确定的代谢控制先天免疫细胞激活。我们之前的许多发现揭示了潜在的治疗靶点针对肺部疾病，包括我们的第二个 NHLBI RO1 中检查干细胞因子和 ILC2 的研究。一我们目前的 NHLBI RO1 拨款正在研究自噬和细胞代谢对先天性的作用免疫细胞功能。我们最近的研究正在解决与训练有素的人相关的其他机制肺内的免疫力，以及改变结构和功能的肺反应的发展肺的完整性。虽然我们将把 2 个 RO1 与不同的主题结合起来，但我们的总体目标是了解疾病期间肺部免疫环境如何发展和维持是核心到我们所有的学习。我们过去和正在进行的调查共同揭示了综合理解不仅与疾病发展过程中的免疫反应有关，而且与早期免疫反应的长期后果有关疾病及其与肺功能和发育改变的关系。使用这个 R35 机制，我们将继续扩大这些将改变范式的研究领域。我们将专注于具体目标包括 1) 确定早期 RSV 诱导的肺部反应如何改变先天免疫细胞表型并引起肺部结构变化，使肺部容易出现过敏/哮喘反应； 2）检查干细胞因子 (SCF) 在改变慢性肺疾病中 ILC2 群体激活中的作用疾病; 3）研究细胞代谢如何改变疾病期间的免疫细胞发育以维持并延长疾病的严重程度。完成这些研究将提供新的见解，建立新的范式，以及推进知识和验证新的治疗方法所需的完整概念验证研究临床疾病的相关机制。