Core C: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

摘要 使用创新的前瞻性思维的鼠标模型和方法，在这个全面的项目 基于发现的Thymus Rejuvenation PPG寻求（i）确定胸腺产生减少背后的机制 和受损的外周血T细胞的维护与老化和压力，和（ii）制定联合战略， 改善这些缺陷，并提高老年人对感染和癌症的免疫防御。的关键 项目确定的机制、途径和治疗靶点在未来项目中的转化潜力， 是小鼠靶点/途径对人类胸腺老化的适用性的概念验证，以及 胸腺功能的集中评估（i. e. sjTREC）。为了满足这一需求， 验证和胸腺功能核心（核心C）已被整合到这个程序项目。在 核心的中心是杜克人类疫苗研究所（DHVI）人类胸腺组织生物库， 含有900多个健康供体的人类胸腺组织（年龄1天至80岁）。Thursday生物银行 由FFPE组织块、速冻组织块和DMSO冷冻保存的胸腺细胞组成， T细胞耗尽的基质。生物库已由核心领导人Greg Sempowski博士维护了15年以上 Sempowski博士和核心合作研究者/病理学家Dr. 劳拉黑尔。黑尔博士的免疫组织化学分析和Sempowski博士的分子分析（i. e.基因 表达和TCR重排）为我们的现代研究奠定了基础。 了解人类胸腺结构和功能在整个生命周期中的变化。核心C将 加速项目确定的小鼠治疗靶点/人体治疗途径的概念验证 胸腺老化/再生，并独立监测胸腺输出，有三个重点具体目标：（SA 1） 定义并表征年龄、性别和表型适用的人胸腺组织样本组，以满足项目要求- 具体的翻译验证需求。提供组织样本的中心组织学和分子学分析; (SA2)为人类和小鼠组织染色提供集中的专家委员会认证的病理学支持， 评分和分析;以及（SA 3）为小鼠sjTREC提供标准化的、质量受控的测定支持 测定。成功地向项目1-4和核心D提供核心C服务将： 这一整体计划，（ii）是整体计划协同作用的关键组成部分，最重要的是，（iii）提供 小鼠靶点/途径对人胸腺适用性的关键概念验证 衰老/年轻化，以改善年龄相关的免疫缺陷，并改善免疫防御， 老年人的感染和癌症。

ABSTRACT Using innovative forward-thinking mouse models and approaches, the Projects in this comprehensive discovery-based Thymus Rejuvenation PPG seek to (i) identify mechanisms behind reduced thymic production and impaired peripheral maintenance of T cells with aging and stress, and (ii) develop combined strategies to ameliorate these defects and improve immune defense against infection and cancer in the elderly. Critical to the translation potential of project-identified mechanisms, pathways and therapeutic targets in future programs, is proof-of-concept verification of applicability of mouse targets/pathways to human thymus aging, and centralized assessment of thymic function (i. e. sjTREC). To meet this need a central Human Target Verification and Thymic Function Core (Core C) has been integrated into this Program Project. At the center of the Core is the Duke Human Vaccine Institute (DHVI) Human Thymus Tissue Biobank, which contains more than 900 healthy-donor human thymus tissues (ages 1 day to 80 years). The Thymus Biobank consists of FFPE tissue blocks, snap-frozen frozen tissue chunks, and DMSO-cryopreserved thymocytes and T cell depleted stroma. The Biobank has been maintained by the Core leader, Dr. Greg Sempowski, for 15+ years and has been extensively characterized by Dr. Sempowski and Core co-investigator/pathologist, Dr. Laura Hale. Dr. Hale's immunohistochemical analysis and Dr. Sempowski's molecular analysis (i. e. gene expression and TCR rearrangement) of tissues from the Biobank laid the foundation for our modern understanding of changes in human thymus architecture and function across the lifespan. Core C will accelerate proof-of-concept verification of project-identified mouse therapeutic targets/pathways in human thymus aging/rejuvenation and independently monitor thymic output with three focused specific aims: (SA1) Define and characterize age, sex and phenotypically applicable human thymus tissues panels to meet project- specific translation verification needs. Provide central histologic and molecular analyses on tissue panels; (SA2) provide centralized expert board-certified pathology support for human and mouse tissue staining, scoring and analysis; and (SA3) provide standardized, quality-controlled assay support for mouse sjTREC assays. Successful delivery of Core C services to Projects 1-4 and Core D will: (i) add considerable value to this overall program, (ii) be a key component of overall program synergy, and most importantly, (iii) provide critical proof-of-concept verification of applicability of mouse targets/pathways to human thymus aging/rejuvenation to ameliorate age-associated immune deficiencies and improve immune defense against infection and cancer in the elderly.