Intestinal tissue intrinsic mechanisms in regulation of GI GVHD

胃肠道 GVHD 调节的肠组织内在机制

基本信息

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
项目类别：
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

项目摘要

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 的总体目标是开发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引起发病和死亡的主要原因细胞移植（HCT）。我们发现了代谢异常的一个令人兴奋的、以前未知的作用同种异体反应性 T 细胞的靶组织是肠上皮细胞 (IEC)，可调节 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) 的严重缺陷，特别是其功能的减少 IEC 中的成分琥珀酸脱氢酶 A (SDHA) 会导致严重的胃肠道 GVHD。这些研究已经确定了 SDHA 在批量 IEC 中的关键作用，该 IEC 由许多不同的子集组成。新兴数据近年来表明，仅少数关键 IEC 子集的数量损失，特别是 Lgr5+ 肠干细胞（ISC）是严重胃肠道 GVHD 的一个关键特征。但 ISC 内在途径对其功能至关重要和维护仍然未知。我们的新初步数据表明线粒体代谢缺陷，在 ISC 中观察到大量 IEC 中线粒体复合物 II (MC II) 的 SDHA 成分减少子集。在这个项目中，我们将在这些令人兴奋和开创性的初步观察的基础上，探索线粒体代谢和生物能量学功能在 ISC 生物学中的作用及其对缓解 GI GVHD 的严重程度。具体来说，我们将测试宿主 Lgr5+ ISC 细胞自主的中心假设线粒体复合物 II 成分的缺乏，SDHA 会放大 GI GVHD。具体目标是：具体目标 (SA) 1：确定线粒体复合物 II 成分 (SDHA) 的功能相关性将 Lgr5+ ISC 宿主至 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，我们的提案将为 ISC 的基础生物学提供开创性的见解，并为减轻 T 细胞介导的靶器官损伤，而不增加更多的免疫抑制，因此具有潜力不仅对同种异体 HCT 具有影响，而且对自身免疫、实体器官移植和 T 细胞介导也有影响疗法。