The role of autophagy gene Atg16L1 in allogeneic hematopoietic stem cell transplantation - Renewal - 1

异基因造血干细胞移植用于治疗多种恶性肿瘤。 和非恶性疾病，涉及从骨髓、血液或脐带血中转移干细胞 来自不同捐赠者的脐带。这一程序的广泛应用受到高比率的限制。 移植物抗宿主病(GVHD)，一种由同种异体反应性T细胞介导的危及生命的疾病 移植。改进程序依赖于确定有助于实现这一点的机制 破坏T细胞的反应性。我们之前在allo-HSCT的临床前小鼠模型中证明了 自噬蛋白ATG16L1对于预防肠道炎症和移植物抗宿主病至关重要。自噬是一种 胞浆物质被运送到溶酶体进行降解的过程，并参与维持 细胞和组织动态平衡。此外，ATG16L1中一个导致编码的常见多态 改变(T300A)与炎症性肠病(IBD)和移植相关的易感性相关 Allo-HSCT患者的死亡率。鉴于T300A变种的高流行率和相关挑战 通过治疗肠道移植物抗宿主病，解决ATG16L1和自噬预防 肠道损伤是研究的重点。 在前一个资助期，我们取得了重大进展，证明了ATG16L1 预防allo-HSCT后肠上皮细胞(IECS)的坏死性下垂。坏死性下垂是一种 程序性坏死作为限制组织损伤的治疗靶点而受到关注 在一系列炎症性疾病中观察到。我们的发现表明自噬和自噬 而坏死性下垂可以作为治疗移植物抗宿主病的靶点，特别是在高危患者中，如藏匿 ATG16L1T300A变种。然而，ATG16L1与坏死性下垂相互作用的分子基础 是模糊的，触发不利信号事件的上游信号需要检查。因此，我们 对应用这些策略所必需的炎症过程缺乏详细的机械理解 给异基因造血干细胞移植的接受者。该提案的目标是研究ATG16L1和自噬如何整合IEC-INTERNAL 和-阻止allo-HSCT后坏死性下垂的外在信号，并确定T300A变体是如何破坏的 这种保护功能。我们预计这些知识将对移植物抗宿主病的发病机制和 告知改善allo-HSCT结局的干预策略。

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of malignant and non-malignant disorders, and involves the transfer of stem cells from the bone marrow, blood, or umbilical cord from a non-identical donor. The widespread application of this procedure is limited by the high rate of graft-versus-host disease (GVHD), a life-threatening condition that is mediated by alloreactive T cells from the transplant. Improving the procedure is dependent on identifying the mechanisms that contribute to this damaging T cell reactivity. We previously demonstrated in a preclinical mouse model of allo-HSCT that the autophagy protein ATG16L1 is essential for preventing intestinal inflammation and GVHD. Autophagy is a process by which cytosolic material is delivered to the lysosome for degradation, and is involved in maintaining cellular and tissue homeostasis. Additionally, a common polymorphism in ATG16L1 leading to a coding change (T300A) is associated with susceptibility to inflammatory bowel disease (IBD) and transplant-related mortality in allo-HSCT patients. Given the high prevalence of the T300A variant and the challenges associated with treating intestinal GVHD, addressing the mechanism by which ATG16L1 and autophagy protect against intestinal damage is a research priority. During the previous funding period, we made significant progress by demonstrating that ATG16L1 prevents necroptosis in intestinal epithelial cells (IECs) following allo-HSCT. Necroptosis is a form of programmed necrosis that has received attention as a therapeutic target for limiting the tissue damage observed in a range of inflammatory diseases. Our findings suggest that the intersection between autophagy and necroptosis can be targeted to treat GVHD, especially in high risk patients such as individuals harboring the ATG16L1T300A variant. However, the molecular basis for the interaction between ATG16L1 and necroptosis is obscure, and the upstream signals that trigger the adverse signaling events require examination. Thus, we lack detailed mechanistic understanding of the inflammatory process that is necessary to apply such strategies to allo-HSCT recipients. The goal of this proposal is to how ATG16L1 and autophagy integrate IEC-intrinsic and -extrinsic signals to block necroptosis following allo-HSCT, and determine how the T300A variant disrupts this protective function. We anticipate this knowledge will yield significant insight into GVHD pathogenesis and inform intervention strategies for improving allo-HSCT outcome.