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.

项目概要 候选人是一名博士后研究员和年轻研究员，致力于发展学术事业 专注于乙醇诱导的分子机制的识别和表征 炎症，导致肝脏耐受性受损和组织损伤。具有很强的氧化背景 与乙醇引起的肝损伤相关的压力和先天免疫，候选人已经开发出特殊的 使用小鼠模型进行拟议研究的专业知识。这些模型系统的使用 补体和过敏毒素在介导肝脏炎症和损伤中的重要作用 由乙醇引起。此外，我们假设 Treg 稳态的改变是受损的原因事件 炎症和损伤的解决。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向独立过渡。职业生涯 提案中描述的发展计划概述了为期 2 年的指导培训，其中包括技术培训 除了旨在促进成功过渡的职业发展活动之外，还开展技能培训 独立。成功后为期 3 年的独立科学和职业发展计划 还概述了助理教授职位的招聘。候选人的导师有一个经过验证的轨迹- 卓越的科学生产力和成功的指导记录，可以为候选人提供坚实的基础 克利夫兰诊所勒纳研究所实验室的研究环境。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，发病率和 死亡率保持不变，患者的长期预后仍然很差。 ALD 是多因素影响的， 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，也是 参与 ALD 的发展，并正在成为一个有吸引力的治疗靶点。我们早期的研究已经 发现异常的、不受控制的补体激活会导致组织损伤；然而，补充 也是肝脏愈合所必需的。这些研究为我们当前的提议奠定了基础：细胞特异性 补体疗法是当前抑制疗法的必要替代方案，可作为一种新型疗法 酒精性肝病（ALD）的治疗。调节性 T 细胞 (Treg) 是炎症消退阶段的关键贡献者 通过分泌大量免疫抑制和促消退细胞因子来维持免疫耐受。 晚期 ALD 患者的外周 Treg 减少，但乙醇改变 T 细胞的机制 体内平衡尚未被研究。  我们的工作假设是补体持续激活是由于 乙醇会导致肝脏中 Treg 的异常调节，从而导致肝脏炎症和组织 受伤。 在三个具体目标中，我们将描述肝脏中乙醇介导的 Treg 分化： 高宾格喂养小鼠，探索过继转移的离体分化iTreg解决问题的能力 肝脏炎症并减少乙醇喂养小鼠的肝损伤，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。我们期望的结果是 这些目标将为未来的乙醇机制研究和临床干预提供坚实的基础 诱发炎症和组织损伤。