Mechanisms of Cardiac Injury Resolution by CX3CR1+ Macrophages

CX3CR1巨噬细胞解决心脏损伤的机制

• 批准号: 10719459
• 负责人: Ronald Joseph Vagnozzi
• 金额: $ 40.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-10 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719459
• 关键词: Ablation; Acceleration; Acute; Acute myocardial infarction; Address; Anti-Inflammatory Agents; Atomic Force Microscopy; Automobile Driving; Biological Assay; Biophysics; Bone Marrow; Bone Marrow Transplantation; CCL2 gene; Cardiac; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Cicatrix; Complex; Cues; Data; Development; Disease; Embryo; Equilibrium; Extracellular Matrix; Fibroblasts; Fibrosis; G-Protein-Coupled Receptors; Gene Delivery; Genetic; Goals; Health; Heart; Heart Injuries; Heart failure; Human; Immune; Immune response; Immunologic Stimulation; Impairment; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Knockout Mice; Knowledge; Ligands; Macrophage; Maintenance; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Organ; Outcome; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Phenotype; Postdoctoral Fellow; Process; Progressive Disease; Proliferating; Property; Proteomics; Resolution; Role; Rupture; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Spleen; Structure; Surface; Surgical Models; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Viral; Work; cardiogenesis; chemokine receptor; coronary fibrosis; cytokine; genome-wide; global health; healing; heart function; immune function; improved; improved outcome; innovation; insight; macrophage-derived chemokine; monocyte; mortality; mouse model; multiple omics; neutrophil; novel; novel therapeutics; prevent; receptor; recruit; repaired; response; response to injury; therapy development; tissue injury; transcriptomics; transplant model; virtual; wound healing

PROJECT SUMMARY/ABSTRACT Heart failure (HF) due to ischemic heart diseases such as myocardial infarction (MI) remains a global health crisis and new therapies to limit the progression to HF after MI are greatly needed. Patient outcomes after MI largely depend on the magnitude, severity, and duration of tissue remodeling - a complex process that involves acute and chronic changes in the structure, function, and cellular makeup of the heart in response to injury. In particular, proper scar formation is required for adequate healing and maintenance of cardiac function. However, the injured heart is predisposed to chronic inflammation and excess scarring, or fibrosis, which promotes cardiac dysfunction, pathological remodeling, and propensity towards HF. It is well recognized that the inflammatory response during post-MI remodeling is a critical determinant of whether scar formation proceeds in a beneficial way to achieve tissue healing or progresses to chronic pathological fibrosis. Inflammation in the post-MI setting is both beneficial and detrimental. For example, acute MI patients given broad-acting anti-inflammatory agents are predisposed to wall rupture due to a muted fibrotic response, highlighting the critical role of inflammatory cells in mediating acute healing through fibroblast activity. Prior work from the proposal PI as a postdoctoral fellow uncovered an unexpected paradigm where activating a subset of innate immune cells, cardiac tissue- resident macrophages (TRMs) expressing the chemokine receptor CX3CR1 (CX3), improved cardiac wound healing and limited fibrosis after MI in a mouse model. This provided proof-of-concept evidence that certain aspects of the inflammatory response can be selectively enhanced to keep post-MI remodeling in balance and improve outcomes. However, the precise cellular signals that drive this pro-healing phenotype in macrophages remain unclear, preventing the development of therapies that harness these beneficial effects of cardiac TRMs. This proposal seeks to address this by elucidating the cellular and molecular mechanisms whereby CX3+ TRMs resolve chronic inflammation and pathological fibrosis in a mouse MI model. To achieve this, we will employ two distinct genetic mouse models to inhibit CX3+ TRMs, genetic macrophage tracking, a well-defined surgical model of MI, and cutting-edge multi-omics, biophysical, and molecular assays of cardiac fibrosis. In Specific Aim 1, we will test the hypothesis that CX3 is required for cardiac TRMs to promote healing post-MI, through attenuating fibroblast expansion and extracellular matrix remodeling. In Specific Aim 2, we leverage a comprehensive spatial transcriptomics and proteomics approach to test the hypothesis that local cardiac microenvironment cues from other subsets of inflammatory macrophages prevent resolution of fibrosis and tissue healing by CX3+ TRMs. Overall our Proposal will determine how CX3+ TRMs act mechanistically to promote myocardial healing and resolve chronic inflammation and fibrosis. These data will reveal potential therapeutic pathways to enhance infarct repair by promoting CX3+ TRM functions. Our long-term goal is to contribute novel insights to better understand and therapeutically modulate cardiac tissue remodeling, thus limiting the progression of HF.

项目摘要/摘要 由心肌梗死(MI)等缺血性心脏病引起的心力衰竭(HF)仍然是一个全球健康问题 迫切需要危象和新的治疗方法来限制心梗后向心力衰竭的进展。心肌梗死后的患者转归 很大程度上取决于组织重塑的幅度、严重性和持续时间--这是一个复杂的过程，涉及 心脏损伤后心脏结构、功能和细胞组成的急性和慢性变化。在……里面 特别是，适当的疤痕形成是充分愈合和维持心脏功能所必需的。然而， 受伤的心脏容易发生慢性炎症和过度的疤痕形成，或纤维化，这会促进心脏 功能障碍、病理性重构和心力衰竭倾向。众所周知，炎症性疾病 心肌梗死后重塑过程中的反应是瘢痕形成是否有益的关键决定因素 达到组织愈合或进展为慢性病理性纤维化的途径。心肌梗塞后环境中的炎症 既有好处，也有坏处。例如，急性心肌梗塞患者服用广效抗炎药 由于纤维化反应减弱，容易发生室壁破裂，突出了炎症的关键作用 细胞通过成纤维细胞的活动介导急性愈合。之前的工作来自提案中的PI作为博士后 一位同事发现了一种意想不到的模式，激活了先天免疫细胞的子集，心脏组织- 表达趋化因子受体CX3CR1(CX3)的常驻巨噬细胞(TRM)改善心脏创伤 小鼠心肌梗死后的愈合和有限的纤维化。这提供了概念验证证据，证明了某些 炎症反应的各个方面可以选择性地增强，以保持心肌梗死后重构的平衡和 改善结果。然而，驱动巨噬细胞这种促愈合表型的精确细胞信号 仍然不清楚，阻碍了利用心脏TRMS的这些有益影响的治疗方法的开发。 这项建议试图通过阐明CX3+TRMS的细胞和分子机制来解决这个问题 解决小鼠心肌梗死模型中的慢性炎症和病理性纤维化。为了实现这一目标，我们将雇用两名 独特的小鼠遗传模型抑制CX3+TRMS，遗传巨噬细胞跟踪，定义明确的手术模型 心肌梗塞，以及心脏纤维化的前沿多组学、生物物理学和分子分析。在具体目标1中，我们 将验证心脏TRMS需要CX3通过减毒促进心肌梗死后愈合的假设 成纤维细胞的扩张和细胞外基质的重塑。在具体目标2中，我们利用一个全面的空间 转录组学和蛋白质组学方法检验局部心脏微环境提示来自 炎症巨噬细胞的其他亚群通过CX3+TRMS阻止纤维化的消退和组织愈合。 总体而言，我们的提案将确定CX3+TRMS如何以机械方式促进心肌愈合和 化解慢性炎症和纤维化。这些数据将揭示潜在的治疗途径以增强 通过促进CX3+TRM功能修复心肌梗死。我们的长期目标是贡献新的见解，以更好地 了解和治疗心脏组织重塑，从而限制心力衰竭的进展。