Host and Microbial Metabolism in Graft versus Host Disease

项目总结/摘要 该计划项目赠款（PPG的）首要目标是使同种异体造血细胞 移植（allo-HCT）对非恶性和恶性血液患者更安全、更有效 疾病为此，它将解决微生物组在减轻移植物严重程度方面的重要性， 抗宿主病（GVHD）是allo-HCT最重要的并发症， allo-HCT。该提案有一个统一的中心主题，特别是要了解肠道的作用， 微生物代谢物与宿主代谢的相互作用以及对肠道GVHD的影响。拟议 项目规划和预算编制小组中的项目是独立的，但也是协同的。它将整合大数据（尖端 技术微生物群落基因组的高通量测序， 代谢组），在定义明确的基础微生物和哺乳动物生物学的机制研究 HCT模型系统和人体，以及重要的是IRB批准的工作台到床边翻译 根据FDA的IND，将这些药物纳入概念验证前瞻性人体临床试验。PPG带来 将来自不同领域的领导者调查人员聚集到一个有凝聚力的团队中， 共同发表，并带来他们的各种专业知识，以改善血液疾病的allo-HCT的结果。 拟议的项目编制补助金将有四个项目和四个核心。所有的项目都是从共同的 项目负责人在过去几年中生成的统一的初步数据集。项目1将 探讨宿主肠上皮细胞（IEC）线粒体与微生物之间的相互作用 在GVHD的鼠模型中，本发明的化合物可用于抑制代谢物，特别是短链脂肪酸（丁酸）。在协同方面， 然而，如果调查不同的路线，项目2将探索宿主-微生物组相互作用依赖的作用， 代谢物，次级胆汁酸（SBAs），对IEC稳态和GVHD的小鼠模型。项目3 将描述关键的微生物和它们在分解特定宿主时所采用的机制 饮食（抗性淀粉）产生丁酸盐和SBAs。饲粮中抗性淀粉对宿主的作用 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讨 临床试验项目4。这些项目将得到最先进的核心的促进，包括 代谢组学，Gnotobiotics小鼠和细菌表型，生物信息学，生物统计学和支持 行政核心。所有研究人员都来自密歇根大学（一个机构）。

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).