Novel regulators of macrophage function to repair sterile inflammation-induced heart injury

巨噬细胞功能的新型调节剂修复无菌炎症引起的心脏损伤

• 批准号: 10622704
• 负责人: Guo-Chang Fan
• 金额: $ 44.55万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622704
• 关键词: Acute; Address; Anti-Inflammatory Agents; Bacteria; Basic Science; Biology; Cardiac; Cardiac Surgery procedures; Cause of Death; Cells; Cellular Membrane; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Data; Development; Diabetic mouse; Exhibits; Genetic; Goals; Heart; Heart Injuries; Heart failure; Human; Immune; Immune System Diseases; Immunologics; Inflammation; Ischemia; Knock-out; Knowledge; Laboratories; Macrophage; Mediator; Membrane; Metabolic Diseases; Mission; Modeling; Molecular; Myelogenous; Myocardial Ischemia; Myocarditis; National Institute of General Medical Sciences; Non-Insulin-Dependent Diabetes Mellitus; Organ; Outcome; Patients; Phenotype; Play; Principal Investigator; Probiotics; Proteins; Public Health; Recombinants; Regulation; Reperfusion Therapy; Research; Role; Signal Pathway; Sterility; Transgenic Organisms; Type 2 diabetic; United States National Institutes of Health; Vesicle; Work; clinical application; disability; extracellular; heart function; improved; member; mouse model; nanodrug; novel; novel therapeutics; programs; repaired; sobriety; translational study; vesicular release

Project Summary The heart is a unique organ from an immunological perspective, as it exhibits extremely low tolerance to damage and inflammation. Growing evidence from basic and clinical research suggests that sterile inflammation, triggered by either acute myocardial ischemia/reperfusion (I/R) or chronic metabolic disorders (i.e., type-2 diabetes), plays a critical role in the development of heart failure, a leading cause of death worldwide. Unfortunately, clinical trials attempting to modulate inflammation in heart failure have been either disappointing or inconsistent and none are yet clinically applicable. This sobering fact reinforces the urgent need to explore new mediators of cardiac inflammation and to better understand their underlying molecular/cellular mechanisms. The studies supported by NIGMS in the principal investigator’s laboratory over the past 5 years have identified several novel mediators and their associated signaling pathways to control immune dysfunction in inflammation-triggered heart injury. First, we discovered that secreted and transmembrane 1a (Sectm1a), a protein highly expressed in immune cells of myeloid lineage, is essential for macrophage (MФ) efferocytosis to clear dead cells from I/R hearts and thereby, restoring cardiac function. Second, using type-2 diabetic (T2D) mice as a chronic low-grade inflammation model, we identified that loss of lipocalin 10 (Lcn10), a poorly characterized member of the lipocalin superfamily, could cause an imbalanced MФ polarization in T2D hearts. Finally, we have made a novel finding that extracellular membrane vesicles (EVs) released by probiotic bacteria can promote MФ efferocytosis, but the underlying mechanism is unclear. Together, these diverse and compelling data provide a strong basis to address three critical knowledge gaps in the study of sterile inflammation-triggered heart injury, which will be examined by three different projects of this MIRA application: 1) what are exact roles and underlying mechanisms of endogenous and exogenous Sectm1a in MФ efferocytosis during acute cardiac I/R? 2) can elevation of Lcn10 in MФs and/or administration of recombinant Lcn10 protein (rLcn10) drive MФs to an anti-inflammatory phenotype for improving cardiac function in T2D mice? and 3) can a probiotic bacterial EV-based nano-drug be developed to modulate MФ function or phenotype for repairing I/R or T2D hearts? The proposed work represents a paradigm shift in MФ biology by defining the roles of three novel modulators (Sectm1a, Lcn10, and bacterial EVs) in the regulation of MФ function and polarization. We will utilize multiple genetic mouse models (MФ-specific transgenic, global knockout, and intercross models) and an adoptive MФ transfer model to determine cardiac outcomes in two sterile inflammation conditions (acute myocardial I/R-induced robust and chronic T2D-triggered low-grade inflammation). These projects, if completed, will significantly push the field of MФ research forward, and offer new therapeutic options for reducing sterile inflammation-caused heart injury, with the hope of improving heart failure patient survival.

项目概要 从免疫学角度来看，心脏是一个独特的器官，因为它对损伤的耐受性极低 和炎症。越来越多的基础和临床研究证据表明，由 无论是急性心肌缺血/再灌注 (I/R) 还是慢性代谢紊乱（即 2 型糖尿病），都起着至关重要的作用 在心力衰竭的发展中发挥作用，心力衰竭是全世界死亡的主要原因。不幸的是，临床试验试图 调节心力衰竭炎症的效果要么令人失望，要么不一致，而且尚未在临床上应用 适用的。这一发人深省的事实强调了探索新的心脏炎症介质和 更好地了解其潜在的分子/细胞机制。 NIGMS主要支持的研究 研究人员的实验室在过去 5 年中已经鉴定出几种新型介质及其相关信号传导 控制炎症引发的心脏损伤中免疫功能障碍的途径。首先，我们发现分泌 跨膜 1a (Sectm1a) 是一种在髓系免疫细胞中高度表达的蛋白质，对于 巨噬细胞 (MФ) 胞吞作用可清除 I/R 心脏中的死亡细胞，从而恢复心脏功能。第二， 使用 2 型糖尿病 (T2D) 小鼠作为慢性低度炎症模型，我们发现脂质运载蛋白 10 的缺失 (Lcn10) 是脂质运载蛋白超家族的一个尚未充分表征的成员，可能会导致 MФ 极化不平衡 T2D 心。最后，我们有了一个新的发现，即益生菌释放的细胞外膜囊泡（EV） 细菌可以促进MФ胞吞作用，但其潜在机制尚不清楚。这些多样化且 令人信服的数据为解决无菌研究中的三个关键知识差距提供了坚实的基础 炎症引发的心脏损伤，将通过此 MIRA 应用程序的三个不同项目进行检查：1) 内源性和外源性 Sectm1a 在 MФ 胞吞作用中的确切作用和潜在机制是什么 急性心脏缺血再灌注？ 2) 可以升高 MФs 中的 Lcn10 和/或施用重组 Lcn10 蛋白 (rLcn10) 驱动 MФ 达到抗炎表型以改善 T2D 小鼠的心脏功能？ 3）益生菌可以 是否可以开发基于细菌 EV 的纳米药物来调节 MФ 功能或表型以修复 I/R 或 T2D 心脏？ 这项工作通过定义三种新型调节剂的作用，代表了 MФ 生物学的范式转变 （Sectm1a、Lcn10 和细菌 EV）在 MФ 功能和极化的调节中的作用。我们将利用多种基因 小鼠模型（MФ特异性转基因、全局敲除和杂交模型）和过继MФ转移模型 确定两种无菌炎症条件下的心脏结果（急性心肌缺血再灌注引起的强和 慢性 T2D 引发的低度炎症）。这些项目如果完成，将极大推动MФ领域的发展 进一步研究，并为减少无菌炎症引起的心脏损伤提供新的治疗选择 提高心力衰竭患者生存率的希望。