Contributions of Myeloid Metabolism to Diastolic Dysfunction

骨髓代谢对舒张功能障碍的影响

• 批准号: 10464077
• 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
• 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/10464077
• 关键词: Acceleration; Area; Basic Science; Behavior; CD36 gene; Cardiac; Cells; Cellular Metabolic Process; Cellular biology; Characteristics; Clinical Research; Data; Disease Progression; EFRAC; Epidemic; Failure; Fatty acid glycerol esters; Functional disorder; Generations; Genes; Heart; Heart failure; Hyperlipidemia; Hypertension; Immune; Immune Targeting; Immunotherapeutic agent; Impairment; Individual; Inflammation; Inflammatory; Link; Lipids; 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; Time; United States National Institutes of Health; Ventricular; cardiometabolism; clinically relevant; combinatorial; comorbidity; coronary fibrosis; deep sequencing; disorder risk; hypertensive; imprint; improved; in vivo; insight; macrophage; metabolomics; mortality; peroxisome; preservation; therapeutic evaluation; therapeutic target; therapeutically effective; tool

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.

Thorp项目摘要 舒张功能障碍（DD）和射血分数保留性心力衰竭（HFpEF）是 发病率和死亡率的重要和外源性原因，几乎没有有效的治疗方法 战略布局增加对HFpEF的了解已被指定为NIH的研究重点。 心脏代谢性HFpEF患者中常见两种风险因素，肥胖和高血压， 并且两者都独立地与炎症和DD相关。炎症的程度是 心脏纤维化和心肌应激程度的关键决定因素， 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，但关于 免疫代谢如何调节DD。骨髓细胞尤其如此， 巨噬细胞，其中DD的免疫代谢贡献是未知的或模糊的。 我们的初步数据表明DD期间巨噬细胞中存在显著的线粒体应激。这是 这是一个将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。目的II将阐明细胞内在的免疫代谢巨噬细胞信号 在DD相关病理过程中调节炎症加速途径的网络。 目的探讨骨髓细胞移植的治疗原理及临床意义 DD期间的代谢。我们的目标将利用新产生的和尖端的实验 工具和方法。总之，这些研究将为我们提供新的见解， DD和免疫代谢的炎症机制和治疗免疫靶点 发信号。