Peripheral T cell maintenance defects with aging

衰老导致外周 T 细胞维持缺陷

• 批准号: 10553995
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 53.06万
• 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 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553995
• 关键词: Adoptive Transfer; Affect; Age; Aging; Atrophic; BMP4; Blood; C57BL/6 Mouse; CCL19 gene; CCL21 gene; Cell Aging; Cell Maintenance; Cells; Cellular biology; Cellularity; Chronology; Coculture Techniques; Collaborations; Complex; Cyclin D1; Dasatinib; Data; Defect; Deterioration; Elderly; Endothelial Cells; Exhibits; Exposure to; Family; Family member; GDF8 gene; GPR39 gene; Genetic; Homeostasis; Human; IL7 gene; Image; Immigration; Immune; Immunity; Impairment; In Vitro; Individual; Infection; Inflammation; Informatics; Interleukin-13; Intervention; Kidney; Lead; Life; Lymphatic; Lymphoid Cell; Maintenance; Messenger RNA; Mitochondria; Molecular; Molecular Target; Mus; Natural regeneration; Neonatal; Operative Surgical Procedures; Organism; Oxidative Stress; Pathway interactions; Peripheral; Population; Production; Proteins; Quercetin; Rejuvenation; Reticular Cell; Role; Secondary to; Signal Transduction; Skin; Stromal Cells; Structure; Supplementation; T-Lymphocyte; TNF gene; Testing; Thymus Gland; Time; Transforming Growth Factor beta; Transgenic Mice; Tumor Necrosis Factor Receptor; Work; age related; aged; candidate identification; capsule; catalase; cell type; draining lymph node; fisetin; functional improvement; immune function; immunosenescence; implantation; improved; in vivo; keratin 5; lymph nodes; lymphoid organ; mouse model; pre-clinical; programs; promoter; response; secondary lymphoid organ; senescence; single-cell RNA sequencing

PROJECT 3- Abstract Naïve T cells (Tn) are produced in the thymus, but require peripheral mechanisms to maintain their homeostasis and function. The premise of this project is that, while thymic involution is a proximal cause of reduced Tn numbers with aging, defects in peripheral maintenance mechanisms in secondary lymphoid organs (SLO) also significantly contribute to immunosenescence. Indeed, in the past project period we have demonstrated that uncorrected defects in peripheral maintenance of Tn cells can powerfully undermine the benefits of reawakening T cell production by the rejuvenated thymus. We further pinpointed a precise chronological sequence of degenerative structural and functional changes in different SLO. This renewal application will continue to dissect mechanistic molecular and cellular basis of SLO aging and regeneration. Based on the order of changes and the evidence supporting cross-talk between Tn cells and SLO stroma, we hypothesize that reduced thymic production of Tn cells reduces trophic signals to SLO stroma, leading to initial stromal niche and network disorganization, that in turn deprives Tn cells of vital trophic signals and initiates a negative feed-forward loop of deterioration in both Tn cell and SLO stromal responses. Our specific aims are: SA1. To elucidate molecular changes in lymph node stroma with aging and IL-7 complex rejuvenation, using a hierarchy of in vitro and in vivo approaches to test a pipeline of candidates identified by miniarray and scRNASeq approaches in the past support period; and SA2. To dissect the intrinsic and extrinsic age-related defects in SLO stromal cells and the role of Tn:stromal crosstalk in LN homeostasis with aging, by examining the roles of oxidative stress, senescent cell accumulation, persistent Tn cell influx and natural polymicrobial exposure (to pet store mice) in LN/SLO aging. Once the defects are dissected, we will formulate interventions that improve peripheral T cell maintenance in aged organisms. These interventions will be tested by Core D, individually or combined with thymic rejuvenation treatments coming from P1&2, for the ability to improve protective immunity against infection. Together with powerful analytical pipelines from Cores A&B, as well as human molecular target verification by Core C, that will correlate age-related changes in mouse T cell and lymphoid organ aging to those in humans, this will provide direct preclinical data that are expected to pave the way for human T cell rejuvenation in older adults.

项目 3-摘要 幼稚 T 细胞 (Tn) 在胸腺中产生，但需要外周机制来维持其 该项目的前提是，胸腺复旧是其近端原因。 随着年龄的增长，二级淋巴器官外周维持机制的缺陷，Tn 数量减少 （SLO）也对免疫衰老有显着贡献。事实上，在过去的项目期间我们发现了这一点。 证明 Tn 细胞外周维护中未纠正的缺陷会严重破坏 我们进一步确定了通过恢复活力的胸腺重新唤醒 T 细胞生产的好处。 不同 SLO 中退行性结构和功能变化的时间顺序。 该更新应用程序将继续剖析 SLO 衰老的分子和细胞基础机制 基于变化的顺序和支持 Tn 细胞与再生之间相互作用的证据。 SLO 基质，我们发现 Tn 细胞胸腺生成减少会减少 SLO 的营养信号 基质，导致最初的基质生态位和网络解体，进而剥夺 Tn 细胞 重要的营养信号并启动 Tn 细胞和 SLO 恶化的负前馈循环 我们的具体目标是： SA1。阐明淋巴结基质随衰老和 IL-7 复合物的分子变化。 复兴，使用体外和体内方法的层次结构来测试由 过去支持时期的微型阵列和 scRNASeq 方法；以及 SA2 的内在和分析。 SLO 基质细胞中与年龄相关的外在缺陷以及 Tn:基质串扰在 LN 中的作用 衰老过程中的稳态，通过检查氧化应激、衰老细胞积累、持久性的作用 LN/SLO 老化过程中 Tn 细胞流入和天然多种微生物暴露（宠物店小鼠）。 一旦缺陷被剖析出来，我们将制定改善外周 T 细胞的干预措施 这些干预措施将由 Core D 单独或与衰老生物体相结合进行测试。 来自 P1 和 2 的胸腺复兴治疗，能够提高针对 结合 Cores A&B 强大的分析流程以及人类分子靶标。 由 Core C 验证，将小鼠 T 细胞和淋巴器官衰老的年龄相关变化与 这将提供直接的临床前数据，有望为人类 T 细胞铺平道路 老年人的返老还童。