Regulation of thymic regeneration by GPR39

项目摘要 胸腺是T细胞生成的主要部位，对损伤极其敏感;但也具有 一种非凡的内源性修复能力然而，即使有持续的胸腺退化， 再生反应日常侮辱，如压力和感染，深刻的胸腺损伤所造成的 常见的癌症治疗和造血细胞移植（HSCT）的调节方案导致 长期T细胞淋巴细胞减少症此外，在同种异体HCT的情况下，胸腺是一个非常重要的器官。 在移植物抗宿主病（GVHD）期间，对同种异体反应性T细胞敏感的靶点。因此， 可以促进HSCT接受者中T细胞重建的疗法是临床优先考虑的。 我们以前已经确定了两种不同的内源性胸腺再生途径， 先天性淋巴样细胞（ILC）产生再生因子IL-22，内皮细胞产生BMP 4 (ECs)两者都通过靶向胸腺上皮细胞（TEC）介导其再生作用。在我们 我们的初步数据表明，锌（Zn），这是第二个最丰富的过渡金属在 身体，是至关重要的T细胞的发展;与小鼠喂养锌缺乏饮食表现出深刻的阻滞 在胸腺细胞的分化和扩张，这是逆转与饲料中补充锌， 饮用水虽然锌是300多种蛋白质的辅因子，并与细胞凋亡有关， 过程，如增殖和凋亡，直接影响T细胞的发展水平， 胸腺细胞，我们发现细胞外锌水平的增加后，损害;和这种易位， 锌可以通过G-受体感受锌直接刺激EC产生与损伤相关的BMP 4 蛋白偶联受体GPR 39。这些研究表明，在稳态条件下， 促进T细胞发育，但在损伤后，胸腺细胞释放的锌能够触发T细胞的发育。 通过刺激GPR 39，有效地作为损伤相关分子， 模式（DAMP）。基于我们的初步数据，我们假设（a）向免疫原性细胞的转变， （B）受损后胸腺细胞中的死亡（ICD）导致Zn的细胞外释放; 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（c） GPR 39信号传导的激活可被开发成促进胸腺功能和T细胞增殖的上级方法。 HSCT后重建。具体而言，我们的建议有以下目的：（1）调查的能力， GPR 39信号传导诱导损伤后内源性再生的多种不同途径;（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 GPR 39信号传导的调节可用作改善HSCT后T细胞重建的手段。 该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，以提高胸腺 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.