Altered Treg Differentiation in ALD: A Novel Role for Anaphylatoxins C3a and C5a

ALD 中 Treg 分化的改变：过敏毒素 C3a 和 C5a 的新作用

• 批准号: 9795355
• 负责人: Rebecca LeAnne Smathers McCullough
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795355
• 关键词: Adoptive Transfer; Affect; Alcohol abuse; Alcohol-Induced Disorders; Alcoholic Hepatitis; Alcoholic Liver Diseases; Anaphylatoxins; Animal Model; Autoimmune Hepatitis; Biological Models; C3AR1 gene; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chemotactic Factors; Chronic; Cirrhosis; Clinic; Clinical; Communication; Complement; Complement 3a; Complement 5a; Complement Activation; Data; Development; Development Plans; Disease; Environment; Ethanol; Event; Fibrosis; Foundations; Future; G-Protein-Coupled Receptors; Health; Hepatic; Hepatocyte; Homeostasis; Hour; Immune; Immune Tolerance; Immunosuppression; Immunosuppressive Agents; Impairment; Inflammation; Injury; Innate Immune Response; Innate Immune System; Interleukin-10; Intervention; Link; Liver; Mediating; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Organ; Oxidative Stress; Pathogenesis; Patients; Peripheral; Phagocytosis; Phase; Population; Positioning Attribute; Postdoctoral Fellow; Primary carcinoma of the liver cells; Production; Productivity; Regulation; Regulatory T-Lymphocyte; Research; Research Institute; Research Personnel; Resolution; Role; Signal Transduction; Solid; T-Lymphocyte; Technical Expertise; Testing; Tissues; Training; Transport Vesicles; United States; Vesicle Transport Pathway; Work; adaptive immune response; alcohol consequences; alcohol exposure; alcohol use disorder; career; career development; cytokine; design; experimental study; extracellular vesicles; feeding; healing; immunoregulation; liver inflammation; liver injury; mortality; mouse model; nanosized; novel; outcome forecast; peripheral tolerance; preventable death; professor; programs; receptor; recruit; restoration; skills training; socioeconomics; stem; targeted treatment; therapeutic target

PROJECT SUMMARY The Candidate is a postdoctoral fellow and young investigator dedicated to developing an academic career focused on the identification and characterization of molecular mechanisms stemming from ethanol-induced inflammation, contributing to impaired liver tolerance and tissue injury. With a strong background in oxidative stress and innate immunity related to ethanol-induced liver injury, the candidate has developed particular expertise in the use of mouse models to conduct the proposed studies. Use of these model systems has revealed and important role for complement, and anaphylatoxins in mediating liver inflammation and injury caused by ethanol. Moreover, we hypothesize that altered Treg homeostasis is a causative event for impaired resolution of inflammation and injury. The Candidate's recent and current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development Plan described in the proposal outlines 2-years of mentored training with includes technical skills training in addition to career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position is also outlined. The Candidate's Mentor has a proven track- record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her lab at the Lerner Research Institute at the Cleveland Clinic. Research plan: Alcoholic liver disease (ALD) is remains a major socioeconomic burden. For decades, rates of morbidity and mortality have remained constant and the long-term prognosis for patients remains poor. ALD is multifactorial, mediated in part by the innate immune system. Complement, a component of innate immunity, is also implicated in the development of ALD and is becoming an attractive therapeutic target. Our early studies have identified that aberrant, uncontrolled complement activation contributes to tissue injury; however, complement is also required for liver healing. These studies provided the foundation for our current proposal: cell-specific complement therapies are a required alternative to current inhibitory therapies, which can be used as a novel treatment for ALD. Regulatory T cells (Treg) are key contributors to the resolution phase of inflammation and maintain immunological tolerance via secretion of a myriad of immunosuppressive and pro-resolving cytokines. Peripheral Treg are reduced in patients with advanced ALD, but the mechanism by which ethanol alters T cell homeostasis has not been investigated.  It is our working hypothesis that sustained complement activation due to ethanol leads to abnormal regulation of Treg in the liver, thus contributing to liver inflammation and tissue injury. In three specific aims, we will characterize ethanol-mediated Treg differentiation in the liver following Gao-Binge feeding in mice, explore the ability of adoptively transferred ex vivo differentiated iTreg to resolve liver inflammation and diminish liver injury in ethanol-fed mice, and assess the ability of extracellular vesicles to stimulate ex vivo differentiation of naïve CD4+ T cells to iTreg and Th17 subtypes. We expect the results of these aims will provide a strong foundation for future mechanistic studies and clinical interventions for ethanol- induced inflammation and tissue injury.

项目摘要 候选人是一名博士后研究员和年轻的研究员，致力于发展学术生涯 重点是识别和表征的分子机制，源于乙醇诱导的 炎症，导致肝脏耐受性受损和组织损伤。有很强的氧化背景 压力和先天免疫与乙醇诱导的肝损伤，候选人已经制定了具体的 使用小鼠模型进行拟议研究的专业知识。使用这些模型系统， 补体和过敏毒素在介导肝脏炎症和损伤中的重要作用 是由乙醇引起的。此外，我们假设Treg稳态的改变是受损的免疫应答的致病事件。 炎症和损伤的消退。候选人最近和当前的工作为她提供了 有机会发展自己的研究计划，并开始她的过渡到独立。职业 建议书中描述的发展计划概述了2年的指导培训，包括技术培训 除了职业发展活动外，还提供技能培训，以促进成功过渡到 独立成功后，独立的科学和职业发展的3年计划 招聘助理教授职位也概述。候选人的导师有一个经过验证的轨道- 优秀的科学生产力和成功的指导记录，并能为候选人提供坚实的 她在克利夫兰诊所勒纳研究所的实验室里进行了研究。研究计划： 酒精性肝病（ALD）仍然是一个主要的社会经济负担。几十年来， 死亡率保持不变，患者的长期预后仍然很差。ALD是多因素的， 部分由先天免疫系统介导。补体是先天免疫的一个组成部分， 与ALD的发展有关，并且正在成为有吸引力的治疗靶点。我们早期的研究 发现异常的、不受控制的补体激活有助于组织损伤;然而，补体激活可导致组织损伤。 也是肝脏愈合所必需的。这些研究为我们目前的建议提供了基础：细胞特异性 补体疗法是当前抑制疗法的必需替代疗法，其可用作新的免疫疗法。 治疗ALD。调节性T细胞（Treg）是炎症消退阶段的关键贡献者， 通过分泌大量的免疫抑制和促消退细胞因子来维持免疫耐受性。 晚期ALD患者外周Treg减少，但乙醇改变T细胞的机制 还没有研究过体内平衡。 我们的工作假设是， 乙醇导致肝脏中Treg的调节异常，从而导致肝脏炎症和组织损伤。 在三个具体的目标中，我们将描述乙醇介导的Treg在肝脏中的分化， 高斌格饲养小鼠，探讨过继转移离体分化iTreg的分辨能力 肝脏炎症和减轻肝脏损伤，并评估细胞外囊泡的能力， 刺激幼稚CD4 + T细胞离体分化为iTreg和Th17亚型。我们期待着 这些目标将为乙醇的未来机制研究和临床干预提供坚实的基础， 引起炎症和组织损伤。