Core-002

核心002

• 批准号: 10618504
• 负责人: Rafi Ahmed
• 金额: $ 3.9万
• 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/10618504
• 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; rational design; 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).

虽然人类免疫反应的研究已经取得了许多进展，但仍存在许多知识空白。 保持。许多感染和免疫介导的疾病局限于特定的组织或器官， 了解组织/器官特异性免疫为此目的，CCHI方案的一个主要总体目标是， 了解记忆CD 8 T细胞在血液、组织和器官中的分化。我们添加了唐娜博士 法伯给我们的CHHI-EVC团队这个周期。她建立了独特的人体组织资源 从已故器官捐献者获得血液和各种组织，因此我们将分析病毒特异性 记忆CD 8 T细胞在死亡器官供体的各种组织中，并解决有关解剖学的问题。 分布和表观遗传，转录和表型概况的病毒特异性CD 8 T细胞引起的活的， 减毒病毒疫苗，并具有最小的抗原再暴露风险。该计划的第二个主要目标是 阐明YFV疫苗接种和病毒感染后“训练免疫”的分子机制， 利用这些知识来开发新的疫苗和免疫疗法。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 适应性免疫应答（例如，通过旁分泌信号传导），相对于先天细胞的细胞内在特性， 与记忆T或B细胞表现出的免疫记忆的经典现象相似？有没有一个增强的 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？如果是这样的话，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 分化和存活，并量化这些网络如何随年龄变化。这将在 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）。由以下各项支持 核心A：给药（Ahmed）;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）。