Project 1: Mitochondrial Bioenergetics and Metabolism of ISCS in GVHD

项目1摘要 P01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)，它仍然是发病率和死亡率的主要原因。在努力实现 这一目标在当前的周期中，我们重点了解了靶组织的作用内在机制 对GVHD的调节的弹性。我们发现了新陈代谢的一个令人兴奋的、以前未知的角色 肠上皮细胞的异常及其微生物代谢产物的调节作用 GI GVHD的严重程度。本周期发表的工作确定了IECS在保护中的关键作用 由丁酸和丙酸等短链脂肪酸调节。未公布的初步数据 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)是导致GI GVHD更严重的因素。 这些研究确定了SDHA在批量IECS中的关键作用，该IECS由许多不同的 子集。近年来出现的数据表明，只有几个关键的IEC子集的数量损失， 特别是，Lgr5+肠干细胞(ISCs)和Paneth细胞亚群是重度GI的关键特征 GVHD。但对其功能和维持至关重要的细胞内在途径仍不清楚。 我们新的初步数据显示，线粒体代谢缺陷，SDHA减少 线粒体复合体II(MC II)的成分也在ISC亚群中观察到，这种成分存在于整体IECS中。在……里面 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在ISC生物学中的作用及其对组织的贡献 在减轻GI GVHD严重程度方面的弹性。具体地说，我们将测试中心假设，细胞 宿主Lgr5+ISCs中线粒体复合体II组分SDHA的自主缺失调节 它的新陈代谢和放大胃肠道移植物抗宿主病。具体目标是：具体目标1：确定功能 宿主Lgr5+ISCs线粒体复合体II组分(SDHA)与GI GVHD及特异性 目的：探讨线粒体复合体II SDHA缺陷对Lgr5+ISC生物学的影响。 总的来说，我们的提案将探索以前未探索的ISC内在途径的生物学，这些途径是 对调节胃肠道移植物抗宿主病严重程度至关重要。重要的是，它在主题上与 P01侧重于ISCs，以新的初步数据为基础，并得到最新技术的支持 核心。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 新的靶点，以减轻胃肠道移植物抗宿主病，而不增加更多的免疫抑制。

PROJECT 1 ABSTRACT The overarching goal of this P01 is to develop non immunosuppressive strategies to prevent and treat gastrointestinal (GI) GVHD, which remains the major cause of morbidity and mortality. In working toward this goal in the current cycle, we focused on understanding the role of target tissue intrinsic mechanisms of resilience in regulation of GVHD. We uncovered an exciting, previously unknown role for metabolic aberrations in the intestinal epithelial cells (IECs) and their regulation by microbial metabolites in regulating the severity of GI GVHD. Work published in the current cycle identified a key role for IECs in the protection mediated by short chain fatty acids such as butyrate and propionate. Unpublished preliminary data generated by us identified a profound defect in mitochondrial complex II (MC II), specifically reduction of its component, succinate dehydrogenase A (SDHA), in IECs that contributed to greater 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 recent years suggest that quantitative loss of only a few key IEC subsets, specifically Lgr5+ intestinal stem cell (ISCs) and Paneth cell subsets are critical features of severe GI GVHD. But the cell 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 also observed in the ISC subset. 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 ISC and its contribution to tissue resilience in mitigating the severity of GI GVHD. Specifically, we will test the central hypothesis that the cell autonomous deficiency of mitochondrial complex II component, SDHA, in the host Lgr5+ ISCs regulates its metabolism and amplifies GI GVHD. The specific aims are: Specific Aim 1: To determine the functional relevance of mitochondrial complex II component (SDHA) in host Lgr5+ ISCs to GI GVHD and Specific Aim 2: To determine the impact of mitochondrial complex II SDHA deficiency on the biology of Lgr5+ ISC. Collectively, our proposal will probe the previously unexplored biology of ISC intrinsic pathways that are critical for regulation of GI GVHD severity. Importantly, it is thematically synergistic with other projects in the P01 with a focus on ISCs, is grounded by novel preliminary data, and is supported by state of the art Cores. If successful, our proposal will provide seminal insights into fundamental biology of ISCs will provide novel targets to mitigate GI GVHD without adding more immune suppression.