Core-002

核心002

• 批准号: 10394367
• 负责人: Rafi Ahmed
• 金额: $ 26.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-02 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394367
• 关键词: Adaptive Immune System; Address; Age; Anatomy; Attenuated Live Virus Vaccine; B-Lymphocytes; Biometry; Blood; CD8-Positive T-Lymphocytes; Cell Aging; Cell Differentiation process; Cell Survival; Cells; Clinical; Development; Epigenetic Process; Exhibits; Future; Genetic Transcription; Genomics; Goals; Human; Immune; Immune response; Immunity; Immunologic Memory; Immunotherapy; Infection; Knowledge; Localized Disease; Mediating; Memory; Molecular; Natural Immunity; Organ; Organ Donor; Paracrine Communication; Phenotype; Property; Signal Transduction; T cell differentiation; T memory cell; T-Lymphocyte; Tissues; Training; Vaccination; Vaccine Design; Vaccines; Virus; Virus Diseases; adaptive immune response; aged; human tissue; minimal risk; monocyte; programs; response; senescence; tissue resource; transcription factor; vaccine-induced immunity

While many strides have been made in the study of human immune responses, numerous knowledge gaps still remain. Many infections and immune-mediated diseases are localized to specific tissues, or organs but little is known about tissue/organ-specific immunity. A major overall goal of this CCHI program to this end is to understand memory CD8 T cells differentiation in the blood, tissues and organs. We have added Dr. Donna Farber to our CHHI-EVC team this cycle. She has established a unique human tissue resource enabling acquisition of blood and various tissues from deceased organ donors, we will therefore analyze virus-specific memory CD8 T cells in various tissues of deceased organ donors and address questions regarding the anatomic distribution and the epigenetic, transcriptional and phenotypic profile of virus-specific CD8 T cells elicited by live- attenuated virus vaccines and with minimal risk of antigenic re-exposure. The second major goal of this program is to elucidate the molecular mechanisms of “trained immunity” after YFV vaccination and viral infection to and harness this knowledge for future development of new classes of vaccines and immunotherapies. We will address the following questions. To what extent is so called “innate memory” caused by the effects of an ongoing adaptive immune response (for example, via paracrine signaling), versus a cell intrinsic property of innate cells, similar to the classic phenomenon of immune memory exhibited by memory T or B cells? Is there an enhanced response of DCs and monocytes, (similar to a memory response in the adaptive immune system), during secondary vaccination or infection? If so, what are the cellular and molecular mechanisms involved? Finally, the third overall goal is to identify signaling and transcription factor (TF) networks associated with T memory cell differentiation and survival and quantify how these networks change with age. This will be achieved in the following projects: Project 1: Immune memory (Ahmed, Hellerstein, Farber); Project 2: Innate immunity (Pulendran, Hellerstein), and Project 3: Immune senescence (Goronzy, Greenleaf). Supported by the following Core A: Adminstration (Ahmed); Core B: Single cell and integrative genomics (Bosinger, Greenleaf); Core C: Clinical and biostatistical (Edupuganti, Kulkanya, Yu).

尽管人类免疫反应的研究已经取得了许多进展，但仍然存在许多知识空白 保持。许多感染和免疫介导的疾病都局限于特定的组织或器官，但很少有 了解组织/器官特异性免疫。为此，CCHI 计划的一个主要总体目标是 了解记忆 CD8 T 细胞在血液、组织和器官中的分化。我们添加了唐娜博士 Farber 本周期向我们的 CHHI-EVC 团队介绍。她建立了独特的人体组织资源，使 从已故器官捐献者处获取血液和各种组织，因此我们将分析病毒特异性 记忆已故器官捐献者各种组织中的 CD8 T 细胞，并解决有关解剖学的问题 活病毒特异性 CD8 T 细胞的分布以及表观遗传、转录和表型特征 减毒病毒疫苗，抗原再次暴露的风险最小。本计划的第二个主要目标 目的是阐明黄热病疫苗接种和病毒感染后“训练免疫”的分子机制 利用这些知识来未来开发新型疫苗和免疫疗法。我们将 回答以下问题。所谓的“先天记忆”在多大程度上是由持续的影响引起的？ 适应性免疫反应（例如，通过旁分泌信号传导），与先天细胞的细胞固有特性相比， 类似于记忆 T 或 B 细胞表现出的经典免疫记忆现象？有没有加强版 DC 和单核细胞的反应（类似于适应性免疫系统中的记忆反应） 二次接种还是感染？如果是这样，涉及的细胞和分子机制是什么？最后， 第三个总体目标是识别与 T 记忆细胞相关的信号传导和转录因子 (TF) 网络 分化和生存，并量化这些网络如何随年龄变化。这将在 以下项目： 项目 1：免疫记忆（Ahmed、Hellerstein、Farber）；项目2：先天免疫 （Pulendran、Hellerstein）和项目 3：免疫衰老（Goronzy、Greenleaf）。由以下机构支持 核心A：行政（艾哈迈德）；核心B：单细胞和整合基因组学（Bosinger、Greenleaf）；核心C： 临床和生物统计学（Edupuganti、Kulkanya、Yu）。