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).

项目概要/摘要 该计划项目拨款（PPG）的总体目标是制造同种异体造血细胞 移植（allo-HCT）对于非恶性和恶性血液患者更安全、更有效 疾病。为此，它将讨论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)，allo-HCT 最显着的并发症，术后预后得到改善 同种异体 HCT。该提案有一个统一的中心主题，特别是了解肠道的作用 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。拟议的 PPG 中的项目既独立又协同。它将整合大数据（尖端 微生物群落基因组高通量测序技术辅以 代谢组），明确定义的基础微生物和哺乳动物生物学的机制研究 HCT 模型系统和人类，而且重要的是 IRB 批准的工作台到床边翻译 其中根据 FDA 的 IND 进行概念验证前瞻性人体临床试验。 PPG带来了 将来自不同领域的领导者调查员聚集在一起，形成一个有凝聚力的团队， 共同发表并汇集他们不同的专业知识来改善血液疾病的异基因 HCT 的结果。 拟议的 PPG 将有四个项目和四个核心。所有项目均源于共同点 过去几年项目负责人生成的统一初步数据集。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 小鼠模型中的短链脂肪酸（丁酸盐）。在协同作用下， 但如果进行调查，项目 2 将探索宿主-微生物组相互作用依赖性的作用 代谢物、次级胆汁酸 (SBA) 对小鼠模型中 IEC 稳态和 GVHD 的影响。项目3 将描述关键微生物及其分解特定宿主所采用的机制 饮食（抗性淀粉）产生丁酸盐和 SBA。膳食抗性淀粉对宿主的作用 将在概念验证中探讨微生物组和代谢组及其对临床 GVHD 的影响 项目 4 中的临床试验。这些项目将由最先进的核心来促进，其中包括 代谢组学、知生小鼠和细菌表型、生物信息学、生物统计学和支持 由行政核心。所有研究人员均来自密歇根大学（单一机构）。

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