Intestinal tissue intrinsic mechanisms in regulation of GI GVHD

胃肠道 GVHD 调节的肠组织内在机制

• 批准号: 10643802
• 负责人: PAVAN REDDY
• 金额: $ 63.58万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-13 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643802
• 关键词: Allogenic; Autoimmunity; Bioenergetics; Biology; Butyrates; Cell Maintenance; Cell Therapy; Cells; Cellular Metabolic Process; Complex; Complication; Critical Pathways; Data; Defect; Development; Electron Transport; Epithelial Cells; Genetic; Glycolysis; Goals; Hematological Disease; Immune; Immunosuppression; Intestinal Graft Versus Host Disease; Intestines; Knockout Mice; LGR5 gene; Maintenance; Malignant - descriptor; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Morbidity - disease rate; Non-Malignant; Organ; Organ Transplantation; Play; Propionates; Publishing; Regulation; Role; Seminal; Severities; Severity of illness; Solid; Succinate Dehydrogenase; T-Lymphocyte; Technology; Testing; Tissues; Volatile Fatty Acids; effective therapy; gastrointestinal; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; insight; intestinal epithelium; leukemia; metabolomics; microbial; mortality; novel; prevent; resilience; response; single cell sequencing; stem cell function; stem cells; tumor

The overarching goal of this R01 is to develop non immunosuppressive strategies to prevent and treat gastrointestinal (GI) GVHD, which remains a major cause of morbidity and mortality from allogeneic hematopoietic cell transplantation (HCT). We have uncovered an exciting, previously unknown role for metabolic aberrations in allo-reactive T cell target tissues, the intestinal epithelial cells (IECs) in regulating the severity of GI GVHD. Our preliminary data identified a profound defect in mitochondrial complex II (MC II), specifically reduction of its component, succinate dehydrogenase A (SDHA), in IECs that contributed to severity of GI GVHD. These studies have identified a key role for SDHA in bulk IECs, which is made up of a number of distinct subsets. Emerging data in the recent years suggest that quantitative loss of only a few key IEC subsets, specifically Lgr5+ intestinal stem cell (ISCs) is a critical features of severe GI GVHD. But the ISC intrinsic pathways that are critical for their function and maintenance remain unknown. Our new preliminary data demonstrate that the mitochondrial metabolic defect, reduction of SDHA component of the mitochondrial complex II (MC II), in the bulk IECs, is observed in the ISC subsets. In this project, we will build on these exciting and seminal preliminary observations and explore the role of mitochondrial metabolic and bioenergetics functions in the biology of ISCs and its contribution to mitigating the severity of GI GVHD. Specifically, we will test the central hypothesis that host Lgr5+ ISCs cell autonomous deficiency of mitochondrial complex II component, SDHA amplifies GI GVHD. The specific aims are: Specific Aim (SA) 1: To determine the functional relevance of mitochondrial complex II component (SDHA) in host Lgr5+ ISCs to GI GVHD. SA 2: Determine the impact of mitochondrial complex II SDHA deficiency on the biology of Lgr5+ ISC. If successful, our proposal will provide seminal insights into fundamental biology of ISCs, provide novel targets to mitigate T cell mediated target organ damage without adding more immune suppression and thus have potential implications not only for allo-HCT but also for autoimmunity, solid organ transplantation and T cell mediated therapies.

R01的总体目标是制定非免疫抑制策略来预防和治疗 胃肠道（GI）GVHD仍然是同种异体造血的发病率和死亡率的主要原因 细胞移植（HCT）。我们发现了代谢畸变的令人兴奋的，以前未知的作用 同种反应T细胞靶组织，肠上皮细胞（IEC）调节GI GVHD的严重程度。我们的 初步数据确定了线粒体复合物II（MC II）的深刻缺陷，特别减少了其 成分，琥珀酸脱氢酶A（SDHA），在IEC中导致GIGVHD的严重程度。这些研究 已经确定了SDHA在批量IEC中的关键作用，该角色由许多不同的子集组成。新兴数据 近年来表明，只有几个关键的IEC子集的定量损失，特别是LGR5+肠干 细胞（ISC）是严重GI GVHD的关键特征。但是ISC内在途径对其功能至关重要 维护仍然未知。我们的新初步数据表明，线粒体代谢缺陷， 在ISC中观察到线粒体复合物II（MC II）的SDHA成分（MC II）的减少 子集。在这个项目中，我们将基于这些令人兴奋和开创的初步观察并探索角色 线粒体代谢和生物能力在ISC的生物学中的功能及其对缓解的贡献 GI GVHD的严重程度。具体来说，我们将测试主机LGR5+ ISCS单元自动群的中心假设 线粒体复合物II成分的缺乏，SDHA放大GIGVHD。具体目的是： 特定目标（SA）1：确定线粒体复合物II组件（SDHA）在中的功能相关性 主机lgr5+ iscs到GI GVHD。 SA 2：确定线粒体复合物II SDHA缺乏对LGR5+ ISC生物学的影响。 如果成功，我们的建议将提供有关ISC基本生物学的精确见解，为 减轻T细胞介导的靶器官损伤而不增加免疫抑制，因此具有潜力 不仅对Allo-HCT，还对自身免疫，实体器官移植和T细胞介导 疗法。