Contributions of Myeloid Metabolism to Diastolic Dysfunction

骨髓代谢对舒张功能障碍的影响

基本信息

批准号：
10689227
负责人：
Edward Benjamin Thorp
金额：
$ 51.47万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-23 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689227
关键词：
Acceleration Area Basic Science Behavior CD36 gene Calibration Cardiac Cells Cellular Metabolic Process Cellular biology Characteristics Clinical Research Data Disease Progression EFRAC Epidemic Fatty acid glycerol esters Functional disorder Generations Genes Heart Heart failure Hyperlipidemia Hypertension Immune Immune Targeting Immunotherapeutic agent Impairment Individual Inflammation Inflammatory Link Lipids Macrophage Metabolic Metabolic Pathway Metabolic syndrome Metabolism Mitochondria Morbidity - disease rate Mus Myelogenous Myeloid Cells Myelopoiesis Myocardial Pathology Pathway interactions Patients Performance Relaxation Research Research Priority Resolution Respiration Risk Factors Role Signal Transduction Stress Testing Therapeutic United States National Institutes of Health Ventricular cardiometabolism clinically relevant combinatorial comorbidity coronary fibrosis deep sequencing disorder risk hypertensive imprint improved in vivo insight metabolomics mortality peroxisome preservation programs synergism therapeutic evaluation therapeutic target therapeutically effective tool

项目摘要

Thorp Project Summary Abstract Diastolic dysfunction (DD) and Heart failure with Preserved Ejection Fraction (HFpEF) are significant and hetetogenous causes of morbidity and mortality with few effective therapeutic strategies. Increased understanding of HFpEF has been earmarked as a NIH research priority. Two risk factors, fat and hypertension, are commonly found in cardiometabolic HFpEF patients, and both independently associate with inflammation and DD. The extent of inflammation is a critical determinant of the degree of cardiac fibrosis and myocardial stress that likely contributes to impaired cardiac performance. As such, the resolution of inflmammation has the potential to ameliorate myocardial pathophysiology. In this context, inflammatory immunometabolic signaling has been linked with to the progression of disease, yet little is known with respect to how immune metabolism regulates DD. This is particuarly true for myeloid cells and especially the macrophage, in which immuonometabolic contriubtions to DD are either unknown or vague. Our preliminary data point to signifcant mitochondrial stress in macrophages during DD. This is an opportunity to combine improved basic understanding of basic cellular mechanisms with the revealing on potential new metabolic therapeutic targets. In our first experimental Aim, we will test the causal associations of myeloid lipid and mitochondrial metabolic pathways during experimental DD. Aim II will elucidate cell-intrinsic immunometabolic macrophage signaling networks that regulate pathways of inflammatory acceleration during DD-associated pathology. Aim III will test the therapeutic proof of principle and clinical relevance of myeloid cell metabolism during DD. Our Aims will leverage newly generated and cutting-edge experimental tools and approaches. Taken together, these studies will provide new insight into the underlying inflammatory mechanisms and therapeutic immune targets of DD and immunometabolic signaling.

索普项目总结摘要舒张功能障碍 (DD) 和射血分数保留的心力衰竭 (HFpEF) 发病率和死亡率的显着且异质的原因几乎没有有效的治疗方法策略。增进对 HFpEF 的了解已被指定为 NIH 研究重点。脂肪和高血压这两个危险因素在心脏代谢性 HFpEF 患者中常见，两者均与炎症和 DD 独立相关。炎症的程度是心脏纤维化程度和心肌应激的关键决定因素可能有助于导致心脏功能受损。因此，炎症的解决有可能改善心肌病理生理学。在这种情况下，炎症免疫代谢信号传导与疾病的进展有关，但人们对其知之甚少免疫代谢如何调节 DD。对于骨髓细胞尤其如此巨噬细胞中，免疫代谢对 DD 的贡献要么是未知的，要么是模糊的。我们的初步数据表明 DD 期间巨噬细胞中存在显着的线粒体应激。这是将提高对基本细胞机制的基本理解与揭示潜在的新代谢治疗靶点。在我们的第一个实验目标中，我们将测试骨髓脂质和线粒体代谢途径的因果关系实验DD。目标 II 将阐明细胞固有的免疫代谢巨噬细胞信号传导 DD 相关病理过程中调节炎症加速途径的网络。目标 III 将测试骨髓细胞的治疗原理和临床相关性证明 DD期间的新陈代谢。我们的目标将利用新产生的尖端实验工具和方法。总而言之，这些研究将为潜在的问题提供新的见解。 DD和免疫代谢的炎症机制和治疗免疫靶点发信号。