Host and Microbial Metabolism in Graft versus Host Disease

移植物抗宿主病中的宿主和微生物代谢

• 批准号: 10650301
• 负责人: PAVAN REDDY
• 金额: $ 219.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650301
• 关键词: Acceleration; Address; Allogeneic Bone Marrow Transplantation; Allogenic; Applications Grants; Big Data; Bile Acids; Bioinformatics; Biological Models; Biology; Biometry; Bone Marrow Transplantation; Butyrates; Cells; Clinical; Clinical Trials; Communication; Complement; Complex; Complication; Data Set; Diet; Documentation; Engineering; Epithelial Cells; Feedback; Fostering; Genomics; Germination; Gnotobiotic; Goals; Hematological Disease; Hematopoietic; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Immunology; Individual; Institution; Institutional Review Boards; Intestinal Graft Versus Host Disease; Intestines; Investigation; Joints; Malignant - descriptor; Martens; Metabolism; Metabolite Interaction; Michigan; Microbe; Microbial Genome Sequencing; Mitochondria; Modification; Molecular; Monitor; Mus; Non-Malignant; Patients; Phenotype; Pre-Clinical Model; Production; Productivity; Program Research Project Grants; Publications; Publishing; Research; Research Personnel; Resistance; Role; Severities; Shapes; Starch; Testing; Time; Translations; Transplant Recipients; Transplantation; Universities; Validation; Volatile Fatty Acids; Work; bench-to-bedside translation; cost efficient; curative treatments; dietary; graft vs host disease; hematopoietic cell transplantation; hematopoietic transplantation; high throughput technology; host microbiome; improved; improved outcome; insight; intestinal epithelium; intestinal homeostasis; meetings; member; metabolome; metabolomics; microbial; microbial community; microbiome; mouse model; novel; operation; programs; prospective; synergism

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).

项目摘要/摘要 计划项目赠款（PPG的）总体目标是制作同种异体造血细胞 对于非恶性和恶性血液的患者，移植（Allo-HCT）更安全，更有效 疾病。为此，它将解决微生物组在缓解移植物的严重程度方面的重要性 与宿主疾病（GVHD），Allo-HCT的最显着并发症，并改善结果 Allo-HCT。该提案具有一个统一的中心主题，特别是为了了解肠的作用 微生物代谢物与宿主代谢和对肠道GVHD的影响。提议 PPG中的项目是独立的，但仍具有协同作用。它将集成大数据（最前沿 技术的高吞吐量测序是微生物群落基因组的高吞吐量测序 代谢组），针对明确定义的基本微生物和哺乳动物生物学的机械研究 HCT模型系统和人类，也重要的是，IRB批准了床头翻译的长凳 其中，这些是在FDA的IND下进行概念性人类临床试验的证明。 PPG带来 从潜水员领域的领导者一起成为一个有凝聚力的团体的调查员一起 一起出版并带来了各种专业知识，以改善血液疾病的Allo-HCT结果。 提出的PPG将有四个项目和四个核心。从共同的所有项目中发芽 统一的初步数据集是由项目负责人过去几年生成的。项目1将 探索宿主肠上皮细胞（IEC）线粒体和微生物之间串扰的作用 代谢物，特别是GVHD鼠模型中的短链脂肪酸（丁酸酯）。在协同作用中 但是，如果投资2，项目2将探索宿主 - 微生物组互动的作用 鼠模型中的IEC稳态和GVHD代谢物，继发性胆汁酸（SBA）。项目3 将描述关键微生物以及它们在分解特定宿主方面所带来的机制 饮食（抗性淀粉）产生丁酸酯和SBA。饮食抗淀粉在宿主中的作用 微生物组和代谢组及其对临床GVHD的影响将在概念证明中探讨 项目4中的临床试验。这些项目将由艺术核心制备，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 通过行政核心。所有调查人员都来自密歇根大学（一个机构）。

项目成果

Feasibility of a dietary intervention to modify gut microbial metabolism in patients with hematopoietic stem cell transplantation.

• DOI: 10.1038/s41591-023-02587-y
• 发表时间: 2023-11
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Riwes, Mary M.;Golob, Jonathan L.;Magenau, John;Shan, Mengrou;Dick, Gregory;Braun, Thomas;Schmidt, Thomas M.;Pawarode, Attaphol;Anand, Sarah;Ghosh, Monalisa;Maciejewski, John;King, Darren;Choi, Sung;Yanik, Gregory;Geer, Marcus;Hillman, Ethan;Lyssiotis, Costas A.;Tewari, Muneesh;Reddy, Pavan
• 通讯作者: Reddy, Pavan