Response of aged thymus to injury and rejuvenation signals

衰老胸腺对损伤和恢复活力信号的反应

• 批准号: 10553993
• 负责人: Jarrod Dudakov
• 金额: $ 63.66万
• 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/10553993
• 关键词: Accounting; Acute; Adrenal Cortex Hormones; Age; Aging; Antigens; Apoptosis; BMP4; Cell Aging; Cell Compartmentation; Cell Death; Cell physiology; Cells; Chronic; Clinical; Collaborations; Complex; Data; Data Set; Defect; Detection; Effectiveness; Endothelial Cells; Epithelium; Equilibrium; G-Protein-Coupled Receptors; GPR39 gene; Generations; Goals; Hematopoietic; Hematopoietic Stem Cell Transplantation; Immune; Immunity; Infection; Inflammatory; Injury; Intervention; Ionizing radiation; Longevity; Lymphoid Cell; Lymphopenia; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Pathway interactions; Patients; Pattern; Peripheral; Population Heterogeneity; Production; Puberty; Purinergic P2 Receptors; Radiation therapy; Regenerative capacity; Regenerative response; Regulation; Rejuvenation; Relapse; Role; Sex Differences; Shock; Signal Transduction; Stimulus; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; Tissues; Transplantation; Work; Zinc; age related; aged; cancer therapy; chemotherapy; conditioning; hematopoietic cell transplantation; immune function; immunogenic cell death; improved; interleukin-22; interleukin-23; juvenile animal; mortality; notch protein; novel; older patient; preclinical study; programs; regenerative; regenerative therapy; repaired; reparative capacity; response; sex; single cell sequencing; targeted treatment; thymic regeneration

PROJECT 1- Abstract Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable capacity for endogenous repair. However, this capacity declines with age and is a major clinical hurdle in elderly patients who receive an immune insult such as that caused by common cancer cytoreductive therapies and the conditioning required for hematopoietic stem cell transplantation (HCT). The premise of this project is that the thymic regenerative response to acute injury is weakened with age and correlates with age-related thymic involution. We will compare and contrast what we know about the cellular and molecular pathways that underpin thymic regeneration in young animals, to the regenerative response in mice during normal thymic aging; and develop rational intervention strategies to improve regeneration in aged mice. In this project, we will comprehensively assess the endogenous regenerative response over lifespan, with particular emphasis on sex differences with age (SA1); perform studies to better understand the underlying mechanisms governing endogenous thymic regeneration and their breakdown in aged mice, focusing on the balance between inflammatory and pro-regenerative signals from dying cells after acute damage (SA2); and develop therapeutic strategies based on these test known and putative strategies to determine their effectiveness in promoting thymopoiesis in aged tissue at baseline or that has undergone damage (SA3). Our project has multiple points of interaction with the other projects and cores of this P01, including a focus on the hematopoietic and non-hematopoietic stromal microenvironment, regulation of Notch-DLL4 interactions, and of utmost importance, a comprehensive shared sequencing dataset that can be leveraged across the program. Together, these aims and interactions support the overarching goal of the P01 to identify the mechanisms responsible for defects in thymic production of naïve T cells with age and develop methods to improve or reverse them. Therefore, the mechanistic and pre-clinical studies outlined have the potential to define important novel pathways underlying thymic regeneration, which could result in clinical approaches to enhance T cell immunity in patients whose thymus has been decimated due to age-related involution.

项目1-摘要 尽管胸腺对感染、休克等急性损伤非常敏感， 或常见的癌症治疗，如细胞减少性化疗或放射治疗，它也有显着的 内源性修复能力。然而，这种能力随着年龄的增长而下降，并且是治疗的主要临床障碍。 接受免疫损伤的老年患者，例如由普通癌症细胞减少疗法引起的免疫损伤 以及造血干细胞移植（HCT）所需的条件。 这个项目的前提是胸腺对急性损伤的再生反应减弱 与年龄相关的胸腺退化。我们将比较和对比我们所知道的 关于细胞和分子途径，支持胸腺再生在年轻的动物， 在正常胸腺老化过程中小鼠的再生反应;并制定合理的干预策略， 促进老年小鼠再生。在本项目中，我们将全面评估内源性 整个生命周期的再生反应，特别强调随年龄的性别差异（SA 1）; 研究，以更好地了解管理内源性胸腺再生的潜在机制， 在老年小鼠中的崩溃，重点是炎症和促再生信号之间的平衡， 急性损伤后死亡细胞（SA 2）;并根据这些已知的测试和 确定其在基线时促进老年组织中胸腺生成的有效性的假定策略， 已受到损害（SA 3）。 我们的项目与此P01的其他项目和核心有多个交互点，包括 专注于造血和非造血基质微环境，Notch-DLL 4的调控 相互作用，最重要的是，一个全面的共享测序数据集， 在整个程序中。总之，这些目标和相互作用支持P01的总体目标，即确定 胸腺产生幼稚T细胞的缺陷与年龄的机制，并开发方法， 改善或逆转它们。因此，概述的机制和临床前研究有可能 定义胸腺再生的重要新途径，这可能导致临床方法， 增强由于年龄相关退化而导致胸腺大量减少的患者的T细胞免疫力。