Host and Microbial Metabolism in Graft versus Host Disease

项目摘要/摘要 该计划项目赠款(PPG)的首要目标是制造异基因造血细胞 移植(allo-HCT)对非恶性和恶性血液患者更安全有效 疾病。为此，它将讨论微生物组在减轻嫁接严重程度方面的重要性- 抗宿主病(GVHD)，allo-HCT最重要的并发症和改善预后 阿洛-HCT。该提案有一个统一的中心主题，特别是理解肠道的作用 微生物代谢产物与宿主代谢的相互作用及其对肠道移植物抗宿主病的影响。建议数 PPG中的项目是独立的，但又是协同的。它将集成大数据(尖端 微生物群落基因组的高通量测序技术 代谢体)，基础微生物和哺乳动物生物学的机制研究 HCT模型系统和人类中，还有重要的是，IRB批准的长凳到床边的翻译 其中，在FDA的IND下进行概念验证的预期人体临床试验。PPG带来了 将来自不同领域的领导者调查人员聚集在一个有凝聚力的团队中， 共同出版，并带来他们的不同专业知识，以改善血液疾病的allo-HCT的结果。 拟议中的PPG将有四个项目和四个核心。所有的项目都是从共同的 统一了项目负责人在过去几年中生成的初步数据集。项目1将 探讨宿主肠上皮细胞(IEC)线粒体与微生物之间的串扰作用 代谢物，特别是GVHD小鼠模型中的短链脂肪酸(丁酸)。在协同中， 然而，如果进行调查，项目2将探索依赖于宿主-微生物组相互作用的作用 代谢产物，次级胆汁酸(SBAs)，对IEC动态平衡和小鼠GVHD的影响。项目3 将描述关键微生物以及它们在分解特定宿主时所采用的机制 饮食(抗性淀粉)以产生丁酸盐和SBAs。饲粮抗性淀粉对寄主的作用 微生物组和代谢组及其对临床GVHD的影响将在概念验证中进行探索 项目4中的临床试验。这些项目将由最先进的核心推动，包括 代谢组学，基因小鼠和细菌表型，生物信息学，生物统计学和支持 由管理核心执行。所有调查人员都来自密歇根大学(单一机构)。

PROJECT SUMMARY/ABSTRACT The program project grant’s (PPG’s) overarching goal is to make allogeneic hematopoietic cell transplantation (allo-HCT) safer and more efficacious for patients with non-malignant and malignant blood diseases. Towards this end, it will address importance of microbiome in mitigating the severity of graft- versus-host disease (GVHD), the most significant complication of allo-HCT and improving outcomes after allo-HCT. The proposal has a unifying central theme, specifically to understand the role of intestinal microbial metabolite interactions with host metabolism and impact on intestinal GVHD. The proposed projects in the PPG are independent and yet synergistic. It will integrate big data (cutting edge technologies high throughput sequencing of genomes of microbial communities complemented by metabolomes), mechanistic studies of fundamental microbial and mammalian biology in well-defined HCT model systems and in humans, and, also importantly an IRB approved bench to bedside translation of these into proof of concept prospective human clinical trial under an IND from FDA. The PPG brings together investigators who are leaders from diverse fields into a cohesive group that has worked, published together and bring their varied expertise to improve outcomes of allo-HCT for blood diseases. The PPG being proposed will have four projects and four cores. All projects germinated from the common unified preliminary datasets that were generated by project leaders over last several years. Project 1 will explore the role of crosstalk between host intestinal epithelial cell (IEC) mitochondria and microbial metabolites, specifically the short chain fatty acid (butyrate) in murine models of GVHD. In synergistic, yet distinct line if investigation, project 2 will explore the role of host-microbiome interaction dependent metabolites, secondary bile acids (SBAs), on IEC homeostasis and GVHD in murine models. Project 3 will delineate the critical microbes and the mechanisms employed by them in breaking down specific host diet (resistant starch) to generate butyrate and SBAs. The role of dietary resistant starch on host microbiome and metabolome and its impact on clinical GVHD will be explored in a proof of concept clinical trial in project 4. These projects will be facilitated by state of the art Cores that include Metabolomics, Gnotobiotics mice and bacterial phenotyping, Bioinformatics, Biostatistics and supported by the Administrative Core. All of the investigators are from University of Michigan (a single institution).