Mechanisms of microbiome-driven cardiac allograft outcomes

微生物组驱动的同种异体心脏移植结果的机制

基本信息

批准号：
10477625
负责人：
Jonathan S Bromberg
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-13 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10477625
关键词：
Address Alloantigen Allografting Anaerobic Bacteria Anti-Inflammatory Agents Antibiotics Atherosclerosis Automobile Driving B-Lymphocytes Bacteria Bacteroides Bifidobacterium Bile Acids Blood Cardiac Cell Nucleus Cells Characteristics Chronic Communities Complex Congestive Heart Failure Data Dendritic Cells Desulfovibrio Diagnosis Diagnostic Drug Exposure Endothelial Cells Endotoxins Epithelial Equilibrium Fermentation Fiber Fibrosis Functional disorder Goals Graft Rejection Graft Survival Health Heart Transplantation Immune Immune response Immunity Immunologics Immunosuppression Immunosuppressive Agents Inflammation Inflammatory Inflammatory Response Injury Intervention Intestines Knowledge Lactobacillus Laminin Lead Ligands Lymphatic Mediating Mesentery Metabolic Metagenomics Mission Molecular Mucous Membrane Mus Myeloid Cells National Institute of Allergy and Infectious Disease Outcome Pathologic Permeability Pharmaceutical Preparations Play Preventive Quality of life Regulatory T-Lymphocyte Reticular Cell Role Serum Small Nuclear RNA Structure Survival Rate T-Lymphocyte Therapeutic Therapeutic Intervention Transplantation Vascular Diseases Volatile Fatty Acids Work acylcarnitine base cell type clinically relevant cytokine dysbiosis fatty acid metabolism fecal microbiota graft failure gut microbiome heart allograft immunoregulation improved interstitial intestinal barrier intestinal epithelium intestinal injury isoimmunity liver injury lymph nodes macrophage microbial microbial community microbiome mortality mouse model novel permissiveness post-transplant pregnant response systemic inflammatory response tool transcriptome transcriptome sequencing transplant model trimethyloxamine

项目摘要

PROJECT SUMMARY Though the one-year survival rate in cardiac transplantation has reached 90-95%, the mortality rate beyond the first year has not changed in the last two decades. Immune-mediated damage remains the primary cause of long-term graft failure. Findings from our and other studies provide the rationale for investigating the gut microbiome as a determinant of post-transplantation outcomes and as a potential tool to induce immune modulation to improve long-term graft outcomes. The goal of this study is to determine the mechanisms by which the gut microbiome impacts allograft outcome. We postulate that the disrupted metabolic activities of the gut microbiome lead to inflammatory responses and intestinal injury via cell-type specific responses in the intestinal cells network, which subsequently modulate alloimmunity and ultimately chronic cardiac graft outcomes. We will take advantage of our clinically-relevant cardiac transplant murine model of chronic rejection with well-characterized alloresponses, induced by pro- or anti-inflammatory bacteria, to determine the alterations in the microbial metabolic activities in Aim 1, then to identify local intestinal barrier changes and the underlying intestinal cell-type specific responses in Aim 2, and finally to characterize systemic alloresponses and graft survival in Aim 3, in order to obtain a holistic understanding of the precise mechanisms of microbiome-driven chronic graft outcomes. The proposed work will identify novel and critical microbiome-based targets for diagnostic application and therapeutic intervention, and discern the complex and bidirectional dialogue between the microbiome and alloimmunity to promote transplant immunologic quiescence and long- term cardiac graft survival.

项目概要虽然心脏移植的一年生存率已达到90-95%，但死亡率却超过了10%。第一年在过去二十年里没有改变。免疫介导的损伤仍然是导致疾病的主要原因长期移植失败。我们和其他研究的结果为研究肠道提供了基本原理微生物组作为移植后结果的决定因素和诱导免疫的潜在工具调节以改善长期移植结果。本研究的目的是通过以下方式确定机制：肠道微生物组影响同种异体移植的结果。我们假设代谢活动被破坏肠道微生物群通过细胞类型特异性反应导致炎症反应和肠道损伤肠细胞网络，随后调节同种免疫并最终调节慢性心脏移植结果。我们将利用我们临床相关的慢性排斥反应的心脏移植小鼠模型具有明确的同种异体反应，由促炎或抗炎细菌诱导，以确定目标 1 中微生物代谢活动的变化，然后确定局部肠道屏障的变化和目标 2 中潜在的肠道细胞类型特异性反应，并最终表征全身同种反应和目标 3 中的移植物存活，以获得对精确机制的全面了解微生物组驱动的慢性移植物结果。拟议的工作将确定基于微生物组的新颖且关键的诊断应用和治疗干预的目标，并辨别复杂和双向的微生物组和同种免疫之间的对话，以促进移植免疫静止和长期免疫心脏移植物的足月存活率。