Mechanisms of microbiome-driven cardiac allograft outcomes

项目摘要 尽管心脏移植的一年存活率已达到90- 95%，但死亡率超过 在过去的二十年里，第一年没有改变。免疫介导的损伤仍然是主要原因， 长期移植失败我们和其他研究的发现为研究肠道提供了理论基础。 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。本研究的目的是确定机制， 肠道微生物组影响同种异体移植结果。我们假设，干扰的代谢活动， 肠道微生物组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物 结果。我们将利用我们的临床相关的心脏移植慢性排斥小鼠模型， 通过由促炎或抗炎细菌诱导的充分表征的同种异体反应，以确定 目的1中微生物代谢活性的改变，然后确定局部肠屏障变化和 目的2中潜在的肠细胞类型特异性反应，最后表征全身同种异体反应 和移植物存活的目标3，以获得一个全面的了解的确切机制， 微生物群驱动的慢性移植物结局。拟议的工作将确定新的和关键的微生物为基础的 诊断应用和治疗干预的目标，并辨别复杂的和双向的 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 长期心脏移植物存活率。

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.