Intestinal tissue intrinsic mechanisms in regulation of GI GVHD

R01的首要目标是开发非免疫抑制策略来预防和治疗 胃肠道(GI)移植物抗宿主病(GVHD)，它仍然是异基因造血的发病率和死亡率的主要原因 细胞移植(HCT)。我们已经发现了一个令人兴奋的，以前未知的作用，代谢异常在 同种异体反应性T细胞靶向组织、肠上皮细胞(IECS)在调节GI GVHD严重程度中的作用。我们的 初步数据发现线粒体复合体II(MC II)存在严重缺陷，特别是其 IECS中的琥珀酸脱氢酶A(SDHA)参与了GI GVHD的严重程度。这些研究 已经确定了SDHA在批量IECS中的关键作用，该批量IECS由许多不同的子集组成。新兴数据 近年来的研究表明，只有几个关键的IEC亚群的数量减少，特别是Lgr5肠干 细胞(ISCs)是重症GI GVHD的重要特征。但对其功能至关重要的ISC内在途径 维护工作仍不得而知。我们新的初步数据表明，线粒体代谢缺陷， 在间质细胞中观察到线粒体复合体II(MC II)中SDHA成分的减少 子集。在这个项目中，我们将建立在这些令人兴奋的和开创性的初步观察结果的基础上，并探索 线粒体代谢和生物能量学在ISCs生物学中的作用及其对缓解 GI GVHD的严重程度。具体地说，我们将测试宿主Lgr5 ISCs细胞自主的中心假设 缺乏线粒体复合体II组分，SDHA可放大GI GVHD。具体目标是： 特异目的(SA)1：确定线粒体复合体II组分(SDHA)的功能相关性 将LGR5 ISC主机连接到GI GVHD。 SA 2：确定线粒体复合体II SDHA缺乏对Lgr5 ISC生物学的影响。 如果成功，我们的建议将为ISCs的基础生物学提供开创性的见解，提供新的目标 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 不仅对异基因血细胞移植有意义，而且对自身免疫、实体器官移植和T细胞介导也有意义 治疗。

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.