RSV-induced DC epigenetic immune modulation

RSV诱导的DC表观遗传免疫调节

• 批准号: 8850782
• 负责人: Nicholas W Lukacs
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850782
• 关键词: 2 year old; Acute; Address; Adult; Affect; Allergens; Allergic Disease; Animals; Antigens; Antiviral Response; Area; Asthma; Cell Maturation; Cell physiology; Cells; Child; Childhood; Chronic; Clinical; Data; Dendritic Cells; Dendritic cell activation; Development; Diagnostic; Disease; Elderly; Environment; Enzymes; Epigenetic Process; Funding; Grant; Health; Hospitalization; Human; ITGAX gene; Immune; Immune response; Immune system; Immunologics; In Vitro; Individual; Infant; Infection; Influenza; Interferons; Knowledge; Leukocytes; Link; Lower Respiratory Tract Infection; Lung; Lung diseases; Mediating; Modeling; Modification; Molecular; Mus; Outcome; Pathogenesis; Pathology; Patients; Pneumonia; Population; Process; Publishing; Recruitment Activity; Regulation; Research; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Respiratory physiology; Respiratory syncytial virus; Role; Sampling; Severities; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Viral; Virus; Virus Diseases; allergic response; chemokine; chemokine receptor; clinically relevant; cytokine; disease phenotype; epidemiologic data; epigenetic regulation; immune function; immunoregulation; in vivo Model; novel; peripheral blood; receptor; respiratory; respiratory infection virus; respiratory virus; response

DESCRIPTION (provided by applicant): Respiratory viral infections in infants can have a significant impact on acute and chronic lung function. The most common respiratory infection in infants and the predominant cause of hospitalization in children (>90%) is respiratory syncytial virus (RSV). The impact that RSV and other respiratory viruses have on establishing the local pulmonary immune environment is not well understood and has a significant effect on long-term pulmonary disease, especially asthma. In the present revised proposal we will extend our focus from the previous funding cycles in which we investigated the role of cytokines and chemokines responsible for the activation and recruitment of leukocytes to the lung. Our published and preliminary data indicate that a key cell responsible for establishing a pathogenic immune environment is the dendritic cell (DC). While RSV, in particular, has been shown to alter DC activation and modulate important innate cytokines, especially type I IFN, little is known regarding the molecular and epigenetic regulation. Our hypothesis for this renewal application is that RSV infection modulates DC and promotes a more pathogenic environment by activation of a specific epigenetic enzyme, KDM5B H3K4 demethylase, that alters key innate cytokines, including type I IFN. Our findings build upon our previous studies and extend our knowledge by investigating a novel area of immunologic research to understand the molecular mechanisms governing the development of pulmonary disease. This proposal will address several important areas, including 1) what role do specific DC subsets have for promoting an altered immune response during RSV infection that enhances development of allergic disease, 2) identify what epigenetic enzymes are induced during RSV infection in DC that correspond to the altered immune environment, 3) examine the function of a specific epigenetic enzyme in vitro to determine its functional role in the process, and 4) determine the mechanism of KDM5B H3K4 demethylase in our in vivo model of RSV infection leading to enhanced allergen-induced disease. Studies using peripheral blood derived cells from adult and infants will enhance the clinical relevance of our findings in murine models and will characterized our findings for correlation with clinical disease.

描述（由申请人提供）：婴儿的呼吸道病毒感染可能会对急性和慢性肺功能产生重大影响。婴儿中最常见的呼吸道感染和儿童住院的主要原因（> 90％）是呼吸道合胞病毒（RSV）。 RSV和其他呼吸道病毒对建立局部肺免疫环境的影响尚不清楚，并且对长期肺部疾病，尤其是哮喘具有重大影响。在本修订的建议中，我们将将重点从以前的资金周期扩展到，在这些周期中，我们研究了负责将白细胞激活和募集到肺部激活和募集的细胞因子和趋化因子的作用。我们发表的和初步的数据表明，负责建立致病环境的关键细胞是树突状细胞（DC）。尤其是RSV已被证明会改变直流活化并调节重要的先天细胞因子，尤其是I型IFN，但关于分子和表观遗传调节知之甚少。我们对这种更新应用的假设是RSV感染调节DC并通过激活特定表观遗传酶KDM5B H3K4脱甲基酶来促进更具致病性的环境，从而改变了关键的先天细胞因子，包括I型IFN。我们的发现以我们先前的研究为基础，并通过研究一项新的免疫学研究领域来扩展我们的知识，以了解管理肺部疾病发展的分子机制。该提案将解决几个重要领域，包括1）特定DC子集在促进RSV感染期间的免疫反应改变的特定作用，从而增强了过敏性疾病的发育，2）确定在DC中诱导的表观遗传酶是什么表观遗传酶，该酶在DC期间诱导了哪些表观遗传酶，该酶与免疫环境的变化相对应，3）确定特定表观中的功能，并确定其功能，并确定其功能，并确定其在VETROD的功能，并确定其在VETRO的功能中的功能。在我们的RSV感染的体内模型中，KDM5B H3K4脱甲基酶导致过敏原诱导的疾病增强。使用来自成年和婴儿的外周血衍生细胞的研究将增强我们在鼠模型中发现的临床相关性，并将表征我们与临床疾病相关的发现。