Regulation of thymic regeneration by GPR39

GPR39 对胸腺再生的调节

• 批准号: 10502128
• 负责人: Jarrod Dudakov
• 金额: $ 62.32万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502128
• 关键词: Acute; Age; Aging; Agonist; Allogenic; Apoptosis; Autoimmune Diseases; BMP4; Biological Availability; Cell Aging; Cell Compartmentation; Cell Death; Cell physiology; Cells; Chronic; Clinical; Communicable Diseases; Data; Development; Diet; Dietary Supplementation; Endothelial Cells; Exhibits; Exposure to; G-Protein-Coupled Receptors; GPR39 gene; Generations; Genetic; Hematopoietic; Hematopoietic Stem Cell Transplantation; Immune; Immunocompetence; Individual; Infection; Injury; Lead; Lymphoid Cell; Lymphopenia; Malignant - descriptor; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Nuclear Accidents; Outcome; Pathway interactions; Patients; Pattern; Persons; Population Heterogeneity; Process; Production; Proteins; Puberty; Radiation Injuries; Radiation therapy; Regenerative capacity; Regenerative pathway; Regenerative response; Regulation; Role; Shock; Signal Transduction; Site; Stress; Stromal Cells; T cell reconstitution; T-Cell Development; T-Lymphocyte; Terrorism; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; Transition Elements; Transplantation; Zinc; Zinc supplementation; age related; aged; base; cancer therapy; chemotherapy; conditioning; drinking water; epithelial repair; extracellular; functional decline; graft vs host disease; hematopoietic cell transplantation; immunogenic cell death; improved; innovation; interleukin-22; mortality; preclinical study; regenerative; repaired; response; restoration; severe injury; small molecule; thymic regeneration; thymocyte; tissue regeneration

PROJECT SUMMARY The thymus, which is the primary site of T cell generation, is extremely sensitive to injury; but also has a remarkable capacity for endogenous repair. However, even though there is continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage caused by common cancer therapies and the conditioning regimes for hematopoietic cell transplantation (HSCT) lead to prolonged T cell lymphopenia. Furthermore, in the context of allogeneic HCT, the thymus is an extremely sensitive target to alloreactive T cells during graft versus host disease (GVHD). Consequently, identification of therapies that can boost T cell reconstitution in recipients of HSCT is a clinical priority. We have previously identified two distinct pathways of endogenous thymic regeneration, centered on the production of the regeneration factors IL-22 by innate lymphoid cells (ILCs), and BMP4 by endothelial cells (ECs); both of which mediate their regenerative effects by targeting thymic epithelial cells (TECs). In our preliminary data we have shown that Zinc (Zn), which is the second most abundant transition metal in the body, is critically important for T cell development; with mice fed a Zn-deficient diet exhibiting a profound block in the differentiation and expansion of thymocytes, which was reversed with dietary supplementation of Zn in drinking water. Although Zn, which is a co-factor for over 300 proteins and has been implicated in cell processes such as proliferation and apoptosis, directly influences T cell development at the level of thymocytes, we found an increase in the levels of extracellular Zn after damage; and that this translocation of Zn could directly stimulate the damage-associated production of BMP4 by ECs via sensing of Zn by the G- protein-coupled receptor GPR39.m These studies suggest that under steady-state conditions Zn is used to promote T cell development, but after damage, Zn released by thymocytes is capable of triggering the regenerative response by ECs by stimulating GPR39, effectively acting as a damage-associated molecular pattern (DAMP). Based on our preliminary data, we hypothesize that (a) a switch toward immunogenic cell death (ICD) in thymocytes after damage leads to the extracellular release of Zn; (b) GPR39-sensing of released zinc is a master regulator of the endogenous regenerative response to acute damage; and (c) activation of GPR39 signaling can be exploited into a superior method to promote thymic function and T cell reconstitution following HSCT. Specifically, our proposal has the following aims: (1) to investigate the ability of GPR39 signaling to induce multiple distinct pathways of endogenous regeneration after damage; (2) to identify the role of thymocyte cell death in initiating the production of regenerative factors; and (3) to evaluate if modulation of GPR39 signaling can be used as a means of improving T cell reconstitution following HSCT. The studies outlined in this proposal not only have the potential to define important pathways underlying tissue regeneration but could also result in innovative clinical approaches to enhance thymic function.

项目概要 胸腺是 T 细胞生成的主要场所，对损伤极其敏感。但也有 卓越的内源修复能力。然而，即使胸腺持续退化， 再生以应对压力和感染等日常侮辱，以及由以下原因引起的严重胸腺损伤 常见的癌症疗法和造血细胞移植（HSCT）的预处理方案导致 长期T细胞淋巴细胞减少。此外，在同种异体 HCT 的背景下，胸腺是一个极其重要的器官。 移植物抗宿主病 (GVHD) 期间同种反应性 T 细胞的敏感靶点。因此，识别 能够促进 HSCT 受者 T 细胞重建的疗法是临床优先考虑的问题。 我们之前已经确定了两种不同的内源胸腺再生途径，集中于 先天淋巴细胞 (ILC) 产生再生因子 IL-22，内皮细胞产生 BMP4 （EC）；两者都通过靶向胸腺上皮细胞（TEC）来介导再生作用。在我们的 初步数据表明，锌（Zn）是自然界中第二丰富的过渡金属。 身体，对于 T 细胞的发育至关重要；喂食缺锌饮食的小鼠表现出严重的阻滞 胸腺细胞的分化和扩张，通过膳食补充锌可以逆转 饮用水。尽管 Zn 是 300 多种蛋白质的辅助因子，并且与细胞 增殖和凋亡等过程，直接影响T细胞水平的发育 胸腺细胞，我们发现损伤后细胞外锌的水平增加；并且这种易位 Zn 可以通过 G- 感测 Zn，直接刺激 ECs 产生与损伤相关的 BMP4。 蛋白质偶联受体 GPR39.m 这些研究表明，在稳态条件下，Zn 用于 促进 T 细胞发育，但在损伤后，胸腺细胞释放的 Zn 能够触发 ECs 通过刺激 GPR39 做出再生反应，有效地充当损伤相关分子 模式（潮湿）。根据我们的初步数据，我们假设（a）转向免疫原性细胞 胸腺细胞损伤后死亡（ICD）导致细胞外释放锌； (b) GPR39-感测 释放的锌是对急性损伤的内源性再生反应的主要调节剂；和（三） GPR39 信号传导的激活可用于促进胸腺功能和 T 细胞的高级方法 HSCT 后重建。具体来说，我们的建议有以下目的：（1）调查 GPR39 信号传导可诱导损伤后多种不同的内源性再生途径； (2) 识别 胸腺细胞死亡在启动再生因子产生中的作用； (3) 评估是否 GPR39 信号传导的调节可用作改善 HSCT 后 T 细胞重建的一种手段。 该提案中概述的研究不仅有可能定义重要的途径 潜在的组织再生，但也可能导致增强胸腺的创新临床方法 功能。