Dissecting the mechanisms of HIV-1 infection and inflammatory signaling in human lymphoid tissue

剖析人类淋巴组织中 HIV-1 感染和炎症信号传导的机制

• 批准号: 10081720
• 负责人: Talia H Swartz
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081720
• 关键词: 3-Dimensional; Architecture; Automobile Driving; Blood; CD4 Positive T Lymphocytes; Cations; Cell Death; Cells; Chronic; Core Facility; Cultured Cells; Cytokine Signaling; DNA; Data; Development; Disease; Environment; Event; Gene Expression; Genomics; Goals; HIV; HIV-1; Health system; Human; Image; Immune; Immunology; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Laboratories; Link; Lymphoid; Lymphoid Tissue; Mediating; Mediator of activation protein; Membrane Fusion; Methods; Modeling; Molecular; Myelogenous; Myeloid Cells; Natural Immunity; P2X-receptor; Pathogenesis; Pathway interactions; Patients; Pattern; Persons; Pharmacology; Physicians; Premature aging syndrome; Prevention approach; Principal Investigator; Process; Property; Purinoceptor; Research Personnel; Role; Scientist; Signal Transduction; Stromal Cells; Structure; Testing; Therapeutic Agents; Tissues; Tonsil; Viral; Viremia; antiretroviral therapy; career; career development; cell type; cellular imaging; cohort; comorbidity; density; improved outcome; inhibitor/antagonist; lymphoid organ; medical schools; novel; novel strategies; novel therapeutics; peripheral blood; preservation; sensor; three dimensional structure; transcriptomics; virology

PROJECT SUMMARY/ABSTRACT HIV-1 infection causing an incurable disease resulting in chronic inflammation that leads to comorbidities. Recent evidence has suggested an important role of purinergic receptors and downstream inflammasome signaling mediators and important contributors to HIV-1 entry and in driving inflammation. Preliminary data indicate that inhibitors of purinergic signaling reduce both HIV-1 infection and inflammatory cytokine signaling. Our goal is to elucidate the role of HIV-1 in mediating inflammatory signaling in lymphoid tissue. This study is the proposal of an early stage investigator physician scientist who will bring together expertise in HIV virology, immunology, and genomics to test the following aims: 1) Differentiating the inflammatory and stromal cell types required for HIV-associated inflammatory signaling in peripheral blood, dissociated tonsils and tonsil blocks. 2) Differentiating patterns of infected and bystander cells through correlative imaging and transcriptomic analysis of infected tonsil blocks. The methods proposed are novel in that they utilize a recently developed ex vivo human tonsil infection model and a single cell imaging and gene expression platform that will allow for understanding the inflammatory signaling that is associated with HIV-1 infection on a single cell level. The investigators and collaborators offer complimentary expertise and the facilities at the Mount Sinai Health System are uniquely capable of supporting these studies with core facilities, large patient cohorts, and institutional support. The Icahn School of Medicine at Mount Sinai has demonstrated commitment to the career development of this early stage principal investigator. The goal is to develop a successful career of the PI as an independent physician scientist in dissecting out the pathogenesis of the HIV-1 infection and downstream signaling in HIV-1 infection with the goal of finding key therapeutic agents in the treatment of HIV-1 infection and inflammation and in understanding and reversing HIV-1 latency in the development of a cure.

项目总结/摘要 HIV-1感染导致无法治愈的疾病，导致慢性炎症，导致合并症。 最近的证据表明，嘌呤受体和下游炎性小体的重要作用 信号传导介质和HIV-1进入和驱动炎症的重要贡献者。初步数据 表明嘌呤能信号传导抑制剂减少HIV-1感染和炎性细胞因子信号传导。 我们的目标是阐明HIV-1在淋巴组织中介导炎症信号的作用。本研究 一个早期阶段的调查医生科学家的建议，他将汇集艾滋病毒病毒学的专业知识， 免疫学和基因组学来测试以下目的：1）区分炎性细胞和基质细胞类型 外周血、分离的扁桃体和扁桃体阻滞中HIV相关炎症信号传导所需。（二） 通过相关成像和转录组学分析区分感染细胞和旁观者细胞的模式 感染的扁桃体组织块所提出的方法是新颖的，因为它们利用最近开发的离体 人类扁桃体感染模型和单细胞成像和基因表达平台，可以实现 在单细胞水平上理解与HIV-1感染相关的炎症信号。的 研究人员和合作者提供免费的专业知识和设施，在西奈山健康 系统能够通过核心设施、大型患者队列和 机构支持。西奈山伊坎医学院已经证明了对职业生涯的承诺 这个早期的主要研究者的发展。目标是发展PI的成功职业生涯， 一个独立的医生科学家在解剖出艾滋病毒-1感染的发病机制和下游 HIV-1感染中的信号传导，目的是找到治疗HIV-1感染的关键治疗剂 和炎症，以及了解和逆转HIV-1潜伏期的治疗方法。