Class 1 Histone Deacetylases Regulate Innate Immune Resistance to Mycobacterium tuberculosis Infection

1 类组蛋白脱乙酰酶调节对结核分枝杆菌感染的先天免疫抵抗力

• 批准号: 9768318
• 负责人: Monica Campo Patino
• 金额: $ 18.93万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-23 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768318
• 关键词: Advisory Committees; Alveolar Macrophages; Anti-inflammatory; Area; Autophagocytosis; Biological Assay; Biomedical Research; Career Mobility; Cell Line; Clinical; Country; Critical Care; Data; Development Plans; Disease; Environment; Epigenetic Process; Exposure to; Faculty; Family; Funding; Gene Expression Profiling; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Goals; Growth; HDAC1 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone Deacetylation; Histones; Household; Human; IL6 gene; Immune response; Immunology; Individual; Infection; Inflammatory; Innate Immune Response; Institution; Interferon Type II; Interleukin-1 beta; Interleukin-6; Laboratories; Lead; Lung; Malignant Neoplasms; Mediating; Medicine; Mentorship; Molecular Biology; Molecular Genetics; Mycobacterium tuberculosis; Natural Resistance; Nitric Oxide; Pathogenesis; Pathway interactions; Peripheral; Phagolysosome; Phenotype; Play; Pulmonary Tuberculosis; Quantitative Trait Loci; Regulation; Research; Research Personnel; Research Training; Resistance; Role; Scientist; Signal Pathway; Techniques; Therapeutic; Training; Training Programs; Tuberculin Test; Tuberculosis; Uganda; United States National Institutes of Health; Universities; Washington; Work; antimicrobial; base; cancer cell; career; career development; cathelicidin; cathelicidin antimicrobial peptide; cohort; cytokine; epigenetic regulation; experience; experimental study; genetic variant; genome-wide; immune resistance; inhibitor/antagonist; insight; latent infection; mRNA Expression; macrophage; member; monocyte; new therapeutic target; non-histone protein; novel; professor; programs; protein expression; response; targeted treatment; transcriptome; translational approach; translational physician; treatment strategy

PROJECT SUMMARY/ABSTRACT This proposal describes a research and training program that will allow Dr. Monica Campo Patino to achieve her long-term goal of becoming an independently funded translational physician-scientist in the area of Mycobacterium tuberculosis (Mtb) immunopathogenesis. Dr. Campo is a faculty member of the Division of Pulmonary and Critical Care Medicine at the University of Washington (UW) and has previous experience in immunology laboratory based techniques. She developed a comprehensive career development plan that builds on her previous training. This includes a research program focused on elucidating the role of epigenetic mechanisms such as histone deacetylation in conferring resistance to Mtb infection. In addition, Dr. Campo included didactic training in the responsible conduct of biomedical research and coursework in molecular biology, epigenetics and career advancement. This work will be conducted under the mentorship of Dr. Thomas R. Hawn, Professor of Medicine at the UW and a diverse scientific and career advisory committee. Dr. Campo will execute her project at the UW, which provides a rich academic environment as one of the top NIH- funded research institutions in the country. Dr. Campo's research focuses on discovering the cellular mechanisms of natural resistance to Mtb infection that can be targeted by new therapies. To achieve this, she leveraged a unique cohort of household contacts of TB cases of which 9% are individuals who resist Mtb infection despite being in a TB endemic area. The histone deacetylase (HDAC) gene family was found to distinguish individuals resistant to infection from those latently infected by using transcriptional profiling. Dr. Campo's preliminary data supports this finding, demonstrating that a Class 1 HDAC inhibitor controls Mtb growth in human monocytes and alveolar macrophages. HDAC inhibitors modulate immune responses in cancer and other inflammatory diseases, but their role in TB host response is unknown. This project's specific aim 1 will determine how class 1 HDACs regulate the mechanisms of innate immune resistance to Mtb by utilizing molecular, genetic and epigenetic techniques in human macrophages. Aim 2 will discover genetic variants that regulate HDAC1 expression and function in macrophages, and will establish whether HDAC1-deficient humans are resistant to Mtb infection. This study will provide new insights into the regulation of resistance to Mtb infection and could lead to a host- directed therapy that targets a specific HDAC and helps to eradicate infection or treat active TB disease.

项目总结/摘要 该提案描述了一项研究和培训计划，将允许莫妮卡·坎波·帕蒂诺博士实现 她的长期目标是成为一个独立资助的翻译医生，科学家在该地区 结核分枝杆菌（Mtb）免疫发病机制。坎波博士是该部门的教职员工 华盛顿大学（UW）的肺部和重症监护医学， 免疫学实验室技术。她制定了一个全面的职业发展计划， 建立在她之前的训练之上这包括一项研究计划，重点是阐明表观遗传的作用， 例如组蛋白脱乙酰化机制赋予对Mtb感染的抗性。此外，坎波博士 包括负责任地进行生物医学研究的教学培训和分子生物学课程。 生物学、表观遗传学和职业发展。该工作将在林博士的指导下进行。 托马斯河Hawn是华盛顿大学医学教授，也是一个多元化的科学和职业咨询委员会。博士 坎波将在华盛顿大学执行她的项目，华盛顿大学作为美国国立卫生研究院的顶级研究机构之一，提供了丰富的学术环境。 资助的研究机构。 博士Campo的研究重点是发现对Mtb感染的天然抵抗力的细胞机制 可以被新的疗法所靶向。为了实现这一目标，她利用了一个独特的家庭接触群体， 结核病病例中，9%的人尽管在结核病流行区，但仍能抵抗结核分枝杆菌感染。的 组蛋白去乙酰化酶（HDAC）基因家族被发现可以区分对感染有抵抗力个体和 通过使用转录谱来检测潜伏感染。坎波博士的初步数据支持这一发现， 证明1类HDAC抑制剂控制人单核细胞和肺泡巨噬细胞中的Mtb生长， 巨噬细胞HDAC抑制剂可调节癌症和其他炎性疾病的免疫应答， 它们在结核宿主反应中的作用尚不清楚。该项目的具体目标1将决定如何1级HDAC 利用分子、遗传和表观遗传学手段调控天然免疫耐药机制 技术在人类巨噬细胞。目标2将发现调节HDAC 1表达的遗传变异， 在巨噬细胞中发挥作用，并将确定HDAC 1缺陷的人类是否对Mtb感染具有抗性。 这项研究将为Mtb感染抗性的调节提供新的见解，并可能导致宿主- 针对特定HDAC的定向治疗，有助于根除感染或治疗活动性结核病。