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

核心 C：T 细胞衰老和再生的胸腺和外周方面

• 批准号: 10226918
• 负责人: Gregory D Sempowski
• 金额: $ 11.15万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226918
• 关键词: Age; Aging; Architecture; Arizona; Biological Assay; Cell Aging; Consult; Consultations; Cryopreservation; Custom; Cytokine Gene; Data Analytics; Databases; Defect; Development; Dimethyl Sulfoxide; Elderly; Ensure; Epithelial; Formalin; Foundations; Freezing; Future; Gene Expression; Gene Expression Profiling; Goals; Histologic; Histology; Human; Image; Immune; Impairment; Individual; Infection; Information Resources Management; Institutes; Leadership; Legal patent; Longevity; Maintenance; Malignant Neoplasms; Modernization; Molecular; Molecular Analysis; Monitor; Mus; Output; Paraffin Embedding; Pathologist; Pathology; Pathway interactions; Peripheral; Phenotype; Production; Quality Control; Quantitative Reverse Transcriptase PCR; Rejuvenation; Research Personnel; Sampling; Scheme; Services; Specimen; Stains; Standardization; Stress; T-Lymphocyte; Thinking; Thymic Tissue; Thymus Gland; Time; TimeLine; Tissue Embedding; Tissue Stains; Tissues; Translations; Universities; Vaccines; Work; age associated immune deficiency; base; biobank; data management; improved; innovation; lymph nodes; mouse development; mouse model; programs; sex; synergism; therapeutic target; thymocyte; tissue processing

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.

抽象的 使用创新的前瞻性鼠标模型和方法，该综合项目 基于发现的胸腺复兴 PPG 寻求 (i) 确定胸腺产生减少背后的机制 以及随着衰老和压力而受损的 T 细胞外周维持，以及 (ii) 制定综合策略 改善这些缺陷并提高老年人对感染和癌症的免疫防御能力。至关重要 项目确定的机制、途径和治疗目标在未来项目中的转化潜力， 是对小鼠靶标/途径对人类胸腺衰老的适用性的概念验证，以及 胸腺功能的集中评估（即 sjTREC）。为了满足这一需求，建立了一个中心人类目标 验证和胸腺功能核心（核心 C）已集成到该计划项目中。在 核心中心是杜克人类疫苗研究所 (DHVI) 人类胸腺组织生物库， 包含 900 多个健康捐赠的人类胸腺组织（年龄从 1 天到 80 岁）。胸腺生物库 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。该生物样本库由核心领导者 Greg Sempowski 博士维护了 15 年以上 Sempowski 博士和核心联合研究员/病理学家 Dr. Sempowski 已对这些年进行了广泛的描述。 劳拉·黑尔。 Hale 博士的免疫组织化学分析和 Sempowski 博士的分子分析（即基因 生物库中组织的表达和 TCR 重排）为我们的现代 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/人类途径的概念验证验证 胸腺老化/恢复活力并独立监测胸腺输出，具有三个重点具体目标：（SA1） 定义和表征年龄、性别和表型适用的人类胸腺组织组以满足项目- 具体翻译验证需求。提供组织板的集中组织学和分子分析； (SA2) 为人类和小鼠组织染色提供集中专家委员会认证的病理学支持， 评分和分析； (SA3) 为小鼠 sjTREC 提供标准化、质量控制的检测支持 化验。向项目 1-4 和核心 D 成功交付核心 C 服务将： (i) 为项目增加可观的价值 该总体计划，(ii) 成为总体计划协同作用的关键组成部分，最重要的是，(iii) 提供 小鼠靶标/途径对人类胸腺的适用性的关键概念验证 衰老/返老还童，改善与年龄相关的免疫缺陷，提高免疫防御能力 老年人的感染和癌症。