Macrophage Circadian Clock Disruption and Inflammation in Heart Failure

心力衰竭中的巨噬细胞生物钟破坏和炎症

基本信息

批准号：
9764124
负责人：
Sumanth D Prabhu
金额：
$ 58.27万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764124
关键词：
ARNTL gene Ablation Agonist Back Behavior Biology Blood Bone Marrow Cardiac Cardiovascular system Cell physiology Cells Characteristics Chronic Clinical Complex Congestive Heart Failure Coronary Data Development Disease Progression E4BP4 Exhibits Fibrosis Functional disorder Genes Genetic Genetic Transcription Heart Heart failure Hematopoietic Human Immune Immune Cell Activation Immunomodulators Infiltration Inflammation Inflammatory Injury Knock-out Knockout Mice Knowledge Left Left Ventricular Remodeling Leukocytes Ligation Link Measures Modeling Molecular Molecular Target Monocytosis Mus Myelogenous Myocardial Infarction Myocardial Ischemia Pathogenesis Pathologic Periodicity Phagocytosis Pharmacology Phenotype Physiological Pilot Projects Play Population Progressive Disease Regulation Role Spleen Testing Therapeutic Tissues Transcription Repressor/Corepressor Translating Up-Regulation Variant Ventricular Wild Type Mouse base beta-Chemokines chemokine chemokine receptor circadian circadian pacemaker clinical practice clinical translation cytokine gamma-Chemokines genetic predictors immune activation immunomodulatory therapies immunoregulation in vivo innovation macrophage molecular clock monocyte novel novel strategies outcome forecast recruit response small molecule therapeutic target transcription factor translational approach

项目摘要

Monocytes and macrophages fundamentally originating from the bone marrow and spleen - pro-inflammatory Ly6Chi monocytes in mice (CD14hi cells in humans) and C-C chemokine receptor 2 (CCR2)+ monocyte-derived macrophages (MDMs) - contribute importantly to tissue injury and left ventricular (LV) remodeling in chronic heart failure (HF), suggesting that these cells may represent therapeutic targets for immunomodulation. Importantly, monocytes and MDMs exhibit circadian variation in multiple functional parameters, in large part due to a robust cell-autonomous molecular clock, which is regulated by the CLOCK/BMAL1 transcriptional complex and subject to an autoregulatory loop involving Rev-erba. Notably, whether the intrinsic circadian clock in monocytes and MDMs is disrupted in HF and its mechanistic link to inflammation and disease progression is entirely unknown. Our pilot studies suggest that monocyte and MDM clock disruption is characteristic of HF, and that monocyte/macrophage Bmal1 (and subsequent Rev-erba/b) loss is associated with upregulation of the immune activator E4bp4, and aggravation of LV remodeling. Based on these data, we hypothesize that the monocyte/MDM clock is dysfunctional in HF, leading to pathological inflammation and cardiac remodeling in a REV-ERBa-linked and E4BP4-dependent manner, and that clock correction is a key molecular target for immunomodulation. Three Aims will test this hypothesis. In Aim 1, we will define alterations in the monocyte circadian clock in HF using a murine coronary ligation model, and test whether monocyte/macrophage clock disruption in myeloid-specific Bmal1 knockout (MBK) mice exacerbates inflammation, innate immune expansion, and LV remodeling during HF. We will also measure inflammatory and clock genes in CD14hi monocytes from humans with HF. In Aim 2, we will delineate the role of monocyte-localized E4bp4, a clock-controlled inflammatory transcription factor and direct target of Rev-erba, in HF by assessing inflammation and LV remodeling after coronary ligation in myeloid-specific E4bp4 knockout (MEK) mice. We will also evaluate whether monocyte E4BP4 suppression rescues the aggravated LV remodeling observed with monocyte/macrophage clock disruption by inducing HF in myeloid-specific Bmal1/E4bp4 double knockout mice. In Aim 3, we will mechanistically establish the potential of targeting the circadian clock as a therapeutic approach in HF, by testing whether treatment with SR9009, a synthetic REV-ERBa/b agonist, favorably modulates monocytes and MDMs and ameliorates or reverses LV remodeling in wild-type mice with established HF, and then in MEK HF mice to determine whether the effects of SR9009 require monocyte/macrophage E4bp4. We will also evaluate the ex vivo activation responses of human HF CD14hi monocytes to the agonist. These studies will further our understanding of how changes in the macrophage circadian clock modulate both inflammation and disease progression in HF, and test novel approaches to immunomodulation using genetic and pharmacological strategies to correct the pathological changes induced by clock disruption.

从根本上起源于骨髓和脾脏 - 促炎的单核细胞和巨噬细胞小鼠（人类的CD14HI细胞）和C-C趋化因子受体2（CCR2）+单核细胞衍生的小鼠中的Ly6chi单核细胞巨噬细胞（MDMS） - 在慢性心脏中对组织损伤和左心室（LV）重塑作出重要贡献失败（HF），表明这些细胞可能代表免疫调节的治疗靶标。重要的是，单核细胞和MDM在多个功能参数中表现出昼夜节律的变化，这在很大程度上是由于强大的细胞自主分子时钟，由时钟/BMAL1转录复合物和受试者调节进行涉及Rev-Erba的自动调节循环。值得注意的是，单核细胞中的固有昼夜节律是否 MDM在HF中受到破坏，其机械与炎症和疾病进展的联系是完全未知的。我们的试点研究表明，单核细胞和MDM时钟破坏是HF的特征，并且单核细胞/巨噬细胞BMAL1（以及随后的Rev-erba/b）损失与免疫的上调有关激活剂E4BP4，并加重LV重塑。基于这些数据，我们假设单核细胞/MDM时钟在HF中功能失调，导致病理炎症和心脏重塑 Rev-Erba链接和E4BP4依赖性方式，该时钟校正是关键的分子目标免疫调节。三个目标将检验这一假设。在AIM 1中，我们将定义单核细胞的改变使用鼠冠状连接模型在HF中的昼夜节律时钟，并测试单核细胞/巨噬细胞时钟是否髓样特异性BMAL1敲除（MBK）小鼠的破坏会加剧炎症，先天免疫膨胀，和HF期间的LV重塑。我们还将测量来自CD14HI单核细胞中的炎症和时钟基因人类与HF。在AIM 2中，我们将描绘单核细胞 - 定位E4BP4的作用，这是一个钟表控制的通过评估炎症和LV，在HF中，炎症转录因子和Rev-Erba的直接目标髓样特异性E4BP4敲除（MEK）小鼠进行冠状动脉连接后进行改造。我们还将评估是否单核细胞E4BP4抑制挽救了用单核细胞/巨噬细胞观察到的加重的LV重塑通过在髓样特异性BMAL1/E4BP4双基因敲除小鼠中诱导HF来破坏时钟。在AIM 3中，我们将通过测试，机械学上确定将昼夜节律作为HF的治疗方法的潜力是否使用SR9009进行合成Rev-Erba/B激动剂的治疗，可调节单核细胞和MDMS 并改善或逆转具有既定HF的野生型小鼠的LV重塑，然后在MEK HF小鼠中进行确定SR9009的影响是否需要单核细胞/巨噬细胞E4BP4。我们还将评估前任人HF CD14HI单核细胞对激动剂的体内激活反应。这些研究将进一步了解巨噬细胞昼夜节律的变化如何调节炎症和疾病 HF的进展，并使用遗传学和药理测试新的免疫调节方法纠正时钟中断引起的病理变化的策略。