Macrophage heterogeneity in atrial remodeling

心房重塑中的巨噬细胞异质性

基本信息

批准号：
10291930
负责人：
Maarten Hulsmans
金额：
$ 58.74万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10291930
关键词：
Address Age Anticoagulation Arrhythmia Atrial Fibrillation Atrial Function Attenuated Bone Marrow Bone Marrow Transplantation Brain Cardiac Cardiac Output Cardiac Surgery procedures Cardiovascular system Cells Clinical Coagulation Process Collagen Complement Computational Biology Computing Methodologies Data Data Set Deposition Deterioration Disease Echocardiography Elderly Electrophysiology (science)Endothelium Fibroblasts Fibrosis Gene Deletion Generations Genes Genetic Goals Growth Heart Heart Atrium Heart failure Heterogeneity Histologic Histology Human Hypertension Immunology In Vitro Incidence Inflammatory Intestines Knock-out Laboratories Lead Left Left Ventricular Remodeling Left atrial structure Leukocytes Marrow Mitral Valve Insufficiency Mus Obesity Operative Surgical Procedures Optics Organ Pathway interactions Patients Pharmacologic Substance Phenotype Play Preparation Prothrombin Publishing Research Rest Risk Factors Role Sampling Science Signal Transduction Source Stroke Structure Testing Therapeutic Therapeutic Embolization Time Tissues Transgenic Mice Transplantation Ventricular Work base clinical risk clinically relevant combat experimental study gain of function hemodynamics human disease immunomodulatory therapies in vivo insight macrophage monocyte mouse model multiphoton microscopy novel osteopontin pre-clinical recruit second harmonic single-cell RNA sequencing small molecule targeted treatment therapeutic evaluation

项目摘要

Atrial remodeling, including dilation and fibrosis, can lead to hemodynamic deterioration and atrial fibrillation. As a consequence, cardiac output declines and atrial clots embolize to the brain, intestines and other organs. While valve surgery and anticoagulation therapy reduce heart failure and stroke, there are nevertheless numerous patients who would benefit from a therapy inhibiting atrial remodeling and its consequences. To address this urgent unmet clinical need, we here propose to investigate the role of macrophages, the fourth most numerous cardiac cell, in atrial remodeling. In preliminary work for this application, i) we developed and validated a new mouse model of atrial remodeling that combines key clinical risk factors, ii) we obtained single- cell RNA-sequencing (scRNA-seq) data from the left atria of mice with atrial remodeling, iii) we determined the ontogeny of atrial macrophages in the steady state and after atrial remodeling, and iv) we established a pipeline for scRNA-seq of human left atrial tissues from patients with atrial disease undergoing heart surgery at MGH. We now propose to test if macrophages form the atria's Achilles' heel promoting atrial remodeling, fibrosis and atrial fibrillation. We will explore the role of macrophage subsets in atrial remodeling using genetic and pharmaceutical cell depletion strategies. We hypothesize that during atrial remodeling, disease-promoting macrophages are derived from blood monocytes while locally sourced macrophages are protective. In these studies, we will profile structural remodeling of the left atrium by echocardiography, hemodynamic and electrophysiological studies, histological analysis and FACS followed by real-time qPCR. Our preliminary scRNA-seq data provide us with a wealth of potential targets to study the causal role of fibrosis-related macrophage genes in atrial remodeling by loss- and gain-of-function studies. We will test the hypothesis that gene deletion in bone marrow-derived cells, i.e. recruited macrophage subsets, attenuates atrial fibrosis by cross-talk to fibroblasts and reduced collagen deposition, leading to less atrial remodeling and reduced inducibility of atrial fibrillation. In a translational aim, we will study macrophage heterogeneity in human atrial tissues by scRNA-seq. We will focus on the comparison between human and mouse scRNA-seq data sets using state-of-the-art computational methods to steer the preclinical discovery work towards pathways that are important in human disease. Our collaborative application unites an interdisciplinary team with expertise in immunology, cardiovascular science and computational biology. While the novel research plan is ambitious, we believe that our preliminary data demonstrate feasibility and provide us with a unique opportunity to study a question with high clinical relevance.

心房重塑，包括扩张和纤维化，可导致血流动力学恶化和心房颤动。结果，心输出量下降，心房血栓栓塞到大脑、肠道和其他器官。虽然瓣膜手术和抗凝治疗可减少心力衰竭和中风，但仍然存在以下问题：许多患者将从抑制心房重塑及其后果的治疗中受益。到为了解决这一紧迫的未满足的临床需求，我们在这里建议研究巨噬细胞的作用，第四个心房重塑中数量最多的心肌细胞。在此应用程序的前期工作中，i) 我们开发并验证了一种新的心房重塑小鼠模型，该模型结合了关键的临床风险因素，ii）我们获得了单- 来自心房重构小鼠左心房的细胞 RNA 测序 (scRNA-seq) 数据，iii) 我们确定了心房巨噬细胞在稳态和心房重塑后的个体发育，iv)我们建立了对来自接受心脏手术的心房疾病患者的人左心房组织进行 scRNA-seq 的管道麻省总医院。我们现在建议测试巨噬细胞是否形成心房的致命弱点，促进心房重塑，纤维化和心房颤动。我们将利用遗传手段探讨巨噬细胞亚群在心房重塑中的作用和药物细胞耗竭策略。我们假设在心房重塑过程中，疾病促进巨噬细胞源自血液单核细胞，而本地来源的巨噬细胞具有保护作用。在这些研究中，我们将通过超声心动图、血流动力学和电生理学研究、组织学分析和 FACS，然后进行实时 qPCR。我们的初步 scRNA-seq 数据为我们提供了大量潜在靶点来研究纤维化相关的因果作用通过功能丧失和获得功能研究来研究巨噬细胞基因在心房重塑中的作用。我们将检验以下假设：骨髓来源细胞（即招募的巨噬细胞亚群）中的基因缺失可通过以下方式减轻心房纤维化：与成纤维细胞的串扰和胶原蛋白沉积的减少，从而减少心房重塑并减少心房颤动的诱发性。在转化目标中，我们将研究人类心房中巨噬细胞的异质性通过 scRNA-seq 检测组织。我们将重点关注人类和小鼠 scRNA-seq 数据集的比较使用最先进的计算方法引导临床前发现工作朝着以下途径发展在人类疾病中具有重要意义。我们的协作应用程序联合了一支具有专业知识的跨学科团队免疫学、心血管科学和计算生物学。虽然新的研究计划雄心勃勃，但我们相信我们的初步数据证明了可行性，并为我们提供了一个独特的机会来研究具有高度临床相关性的问题。