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.

项目摘要尽管心脏移植的一年生存率已达到90-95％，但死亡率超过在过去的二十年中，第一年没有改变。免疫介导的损伤仍然是长期移植失败。我们和其他研究的发现提供了研究肠道的基本原理微生物组是移植后结果的决定因素，也是诱导免疫的潜在工具调节以改善长期移植结果。这项研究的目的是确定肠道微生物组会影响同种异体移植结果。我们假设，破坏了代谢活动的破坏肠道微生物组导致通过细胞类型的特异性反应导致炎症反应和肠道损伤肠道细胞网络，随后调节同种免疫力并最终调节慢性心脏移植结果。我们将利用与临床相关的心脏移植鼠模型的慢性排斥模型由促疾病或抗炎细菌诱导的充分表征的同种酶，以确定 AIM 1中微生物代谢活动的改变，然后确定局部肠道屏障的变化和 AIM 2中的基本肠细胞类型特异性反应，最后表征全身性同种酶 AIM 3中的嫁接生存，以便获得对精确机制的整体理解微生物组驱动的慢性移植结果。拟议的工作将确定基于新颖和关键的微生物组诊断应用和治疗干预的目标，并辨别复合物和双向微生物组与同种免疫性之间的对话，以促进移植免疫静止和长期术语心脏移植生存。