Regulation of thymic regeneration by GPR39

项目总结 胸腺是T细胞产生的主要部位，对损伤极其敏感；但也有 非凡的内源性修复能力。然而，即使有持续的胸腺退化和 在应对压力和感染等日常侮辱时再生，造成严重的胸腺损伤 常见的癌症治疗和造血细胞移植(HSCT)的调节方案导致 延长的T细胞淋巴细胞减少症。此外，在同种异体红细胞移植的背景下，胸腺是一种极端的 移植物抗宿主病(GVHD)中对同种异体反应性T细胞的敏感靶点。因此，确定 能够促进HSCT受者T细胞重建的治疗是临床上的优先事项。 我们之前已经确定了两条不同的内源性胸腺再生途径，集中在 天然淋巴样细胞产生IL-22和内皮细胞产生骨形态发生蛋白4 (ECS)；两者都通过靶向胸腺上皮细胞(TECs)来调节其再生效应。在我们的 初步数据表明，锌是地球上第二丰富的过渡金属。 身体，对T细胞发育至关重要；喂食缺锌饮食的小鼠表现出严重的阻碍 在胸腺细胞的分化和扩增中，锌的补充逆转了这一作用 喝水。尽管锌是300多种蛋白质的辅助因子，并已被认为与细胞 增殖和凋亡等过程直接影响T细胞的发育 胸腺细胞，我们发现细胞外锌水平在损伤后增加；这种移位 锌可直接刺激内皮细胞损伤相关的BMP4的产生，其机制是通过G- 蛋白质偶联受体GPR39.m这些研究表明，在稳态条件下，锌被用于 促进T细胞发育，但在受损后，胸腺细胞释放的锌能够触发 内皮细胞刺激GPR39的再生反应，有效地发挥损伤相关分子的作用 图案(潮湿)。根据我们的初步数据，我们假设(A)转向免疫原性细胞 胸腺细胞损伤后的死亡(ICD)导致细胞外锌的释放；(B)GPR39-感知 释放的锌是对急性损伤的内源性再生反应的主要调节器；和(C) GPR39信号的激活可以成为促进胸腺功能和T细胞的一种更好的方法 HSCT后的重建。具体地说，我们的建议有以下目的：(1)调查 GPR39信号在损伤后诱导多条不同的内源再生途径；(2)鉴定 胸腺细胞死亡在启动再生因子产生中的作用；以及(3)评估是否 GPR39信号的调制可以作为促进HSCT后T细胞重建的一种手段。 这项提案中概述的研究不仅有可能确定重要的途径 潜在的组织再生，但也可能导致创新的临床方法，以增强胸腺 功能。

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.