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

自噬基因Atg16L1在异基因造血干细胞移植中的作用 - Renewal - 1

• 批准号: 10410421
• 负责人: Ken Hashigiwa Cadwell
• 金额: $ 71.93万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410421
• 关键词: Address; Affect; Allogenic; Animal Model; Application procedure; Attention; Autophagocytosis; Bacterial Translocation; Blood; Bone Marrow; Bone Marrow Stem Cell; Cell Death; Cell Survival; Cell Transplantation; Cellular biology; Cessation of life; Coculture Techniques; Code; Complication; Cues; Culture Techniques; Disease; Disease Outcome; Epithelial; Epithelial Cells; Event; Funding; Gastrointestinal tract structure; Generations; Genes; Genetic Polymorphism; Goals; Hematopoietic Stem Cell Transplantation; High Prevalence; Homeostasis; Human; Immune; In Vitro; Incubated; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inhibition of Apoptosis; Intervention; Intestinal Graft Versus Host Disease; Intestines; Knock-in Mouse; Knowledge; Lead; Life; Link; Lymphocyte; Lysosomes; Malignant - descriptor; Mediating; Membrane; Modeling; Molecular; Mucous Membrane; Mus; Necrosis; Non-Malignant; Organ; Organoids; Outcome; Paneth Cells; Pathogenesis; Pathway interactions; Patients; Predisposition; Procedures; Process; Proteins; Recycling; Regimen; Research Priority; Role; Signal Transduction; T-Lymphocyte; Tissue Grafts; Tissues; Transplant Recipients; Transplantation; Umbilical cord structure; Variant; Vesicle; antimicrobial; cancer type; cell killing; chemotherapy; clinical practice; conditioning; graft vs host disease; gut inflammation; gut microbiota; high risk; improved; insight; intestinal epithelium; irradiation; microbiota; mortality; mortality risk; mouse model; mucosal site; novel; pre-clinical; prevent; response; risk variant; targeted treatment; therapeutic target; three dimensional cell culture

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.

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、血液或脐带转移干细胞 来自不同捐赠者的脐带。该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。改进程序取决于确定有助于此的机制 破坏 T 细胞反应性。我们之前在异基因造血干细胞移植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 GVHD 至关重要。自噬是一种 胞质物质被递送至溶酶体进行降解的过程，并参与维持 细胞和组织稳态。此外，ATG16L1 中的常见多态性导致编码 变化（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 变体的高流行率和相关挑战 治疗肠道 GVHD，解决 ATG16L1 和自噬预防的机制 肠道损伤是研究的重点。 在上一个资助期间，我们通过证明 ATG16L1 取得了重大进展 预防异基因 HSCT 后肠上皮细胞 (IEC) 的坏死性凋亡。坏死性凋亡是一种形式 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。我们的研究结果表明自噬之间的交叉 坏死性凋亡可以作为治疗 GVHD 的目标，特别是对于高危患者，例如携带 GVHD 的个体 ATG16L1T300A 变体。然而，ATG16L1 与坏死性凋亡之间相互作用的分子基础 是模糊的，触发不良信号事件的上游信号需要检查。因此，我们 缺乏对应用此类策略所需的炎症过程的详细机制了解 致同种异体造血干细胞移植（allo-HSCT）接受者。该提案的目标是ATG16L1和自噬如何整合IEC-intrinsic - 阻止同种异体造血干细胞移植后坏死性凋亡的外在信号，并确定 T300A 变体如何破坏 这种保护功能。我们预计这些知识将有助于深入了解 GVHD 发病机制和 为改善异基因造血干细胞移植结果的干预策略提供信息。

项目成果

Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation.

细菌和噬菌体联合体与接受干细胞移植的患者的保护性肠道代谢产物有关。

• 发表时间: 2024-01
• 影响因子: 22.7
• 作者: Thiele Orberg, Erik;Meedt, Elisabeth;Hiergeist, Andreas;Xue, Jinling;Heinrich, Paul;Ru, Jinlong;Ghimire, Sakhila;Miltiadous, Oriana;Lindner, Sarah;Tiefgraber, Melanie;Göldel, Sophia;Eismann, Tina;Schwarz, Ali;Göttert, Sascha;Jarosch, Sebast
• 通讯作者: Jarosch, Sebast