Intestinal tissue intrinsic mechanisms in regulation of GI GVHD

本R01的总体目标是开发非免疫抑制策略，以预防和治疗 胃肠道（GI）GVHD，其仍然是同种异体造血干细胞移植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，代谢畸变， 同种异体反应性T细胞靶组织，肠上皮细胞（IEC）在调节GI GVHD的严重程度。我们 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 在IEC中，琥珀酸脱氢酶A（SDHA）是导致GI GVHD严重程度的主要成分。这些研究 已经确定了SDHA在批量IEC中的关键作用，批量IEC由许多不同的子集组成。新出现的数据 近年来的研究表明，只有少数关键的IEC亚群，特别是Lgr 5+肠干细胞的定量丢失， 细胞（ISCs）是严重GI GVHD的关键特征。但是ISC的内在通路对它们的功能至关重要， 和维护仍然未知。我们新的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组分减少， 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和探索的作用， 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减轻 GI GVHD的严重程度。具体来说，我们将测试中心假设，即宿主Lgr5 + ISCs细胞自主 线粒体复合物II组分的缺乏，SDHA放大GI GVHD。具体目标是： 具体目标（SA）1：确定线粒体复合物II组分（SDHA）在 宿主Lgr5 + ISC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。 如果成功的话，我们的提案将为ISC的基础生物学提供开创性的见解， 减轻T细胞介导的靶器官损伤而不增加更多的免疫抑制，因此具有潜在的 不仅对allo-HCT，而且对自身免疫、实体器官移植和T细胞介导的 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.