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).

尽管在人类免疫复杂的研究中已经取得了许多进步，但仍有许多知识差距 保持。许多感染和免疫介导的疾病本地化于特定组织或器官，但几乎没有 有关组织/器官特异性免疫的已知。该CCHI计划的主要总体目标是 了解记忆CD8 T细胞分化血液，组织和器官。我们添加了唐娜博士 这个周期为我们的Chhi-evc团队而言。她建立了一个独特的人体组织资源 因此，我们将从已故器官供体中获取血液和各种组织，因此我们将分析病毒特异性 记忆的CD8 T细胞在已故器官供体的各种组织中，并解决有关解剖学的问题 通过活体引起的病毒特异性CD8 T细胞的分布和表观遗传，转录和表型特征 病毒疫苗减弱，抗原再暴露的风险很小。该计划的第二个主要目标 是为了阐明YFV疫苗接种和病毒感染后“受过训练的免疫”的分子机制 利用这些知识，以未来开发新的疫苗和免疫疗法。我们将 解决以下问题。所谓的“先天记忆”在多大程度上是由正在进行的效果引起的 自适应免疫响应（例如，通过旁分泌信号传导）与先天细胞的细胞内在特性， 类似于记忆T或B细胞暴露的免疫记忆的经典现象？有增强的 DC和单核细胞的响应（类似于自适应免疫系统中的记忆响应）， 继发疫苗接种还是感染？如果是这样，涉及什么细胞和分子机制？最后， 第三个总目标是识别与T存储器单元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着年龄的增长而变化。这将在 以下项目：项目1：免疫记忆（艾哈迈德（Ahmed，Hellerstein，Farber））；项目2：先天免疫 （Pulendran，Hellerstein）和项目3：免疫感应（Goronzy，Greenleaf）。由以下支持 核心A：管理（艾哈迈德）；核心B：单细胞和综合基因组学（Bosinger，Greenleaf）；核心C： 临床和生物统计学（Edupuganti，Kulkanya，YU）。