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

异基因造血干细胞移植（allo-HSCT）用于治疗多种恶性肿瘤， 和非恶性疾病，并涉及从骨髓，血液或脐带中转移干细胞 一个不一样的捐赠者的脐带这一程序的广泛应用受到高发病率的限制。 移植物抗宿主病（GVHD），一种由来自移植物的同种异体反应性T细胞介导的危及生命的疾病， 移植改进这一程序取决于确定有助于这一点的机制 破坏T细胞反应性我们先前在allo-HSCT的临床前小鼠模型中证明， 自噬蛋白ATG 16 L1对于预防肠道炎症和GVHD是必需的。自噬是一 胞质物质被运送到溶酶体降解的过程，并参与维持 细胞和组织内稳态。此外，ATG 16 L1中常见的多态性导致编码 变化（T300 A）与炎症性肠病（IBD）易感性和移植相关性相关 allo-HSCT患者的死亡率。鉴于T300 A变异的高流行率和相关的挑战， 治疗肠道GVHD，解决ATG 16 L1和自噬保护肠道GVHD的机制。 肠道损伤是研究重点。 在上一个资助期间，我们取得了重大进展，证明了ATG 16 L1 防止allo-HSCT后肠上皮细胞（IEC）坏死性凋亡。坏死性上睑下垂是 程序性坏死作为限制组织损伤的治疗靶点受到关注 在一系列炎症性疾病中观察到。我们的发现表明自噬与 和坏死性凋亡可以靶向治疗GVHD，特别是在高风险患者中，例如患有 ATG 16 L1 T300 A变体。然而，ATG 16 L1和坏死性凋亡之间相互作用的分子基础 是模糊的，并且触发不利信号事件的上游信号需要检查。因此我们 缺乏对应用这些策略所必需的炎症过程的详细机制理解 异基因造血干细胞移植受者该提案的目标是研究ATG 16 L1和自噬如何整合IEC-内在 和-外源性信号阻断allo-HSCT后的坏死性凋亡，并确定T300 A变体如何破坏 这种保护功能。我们预期这些知识将产生对GVHD发病机制的重要见解， 为改善allo-HSCT结果提供信息干预策略。

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.