Contributions of Myeloid Metabolism to Diastolic Dysfunction

Thorp项目摘要 舒张期功能不全(DD)和射血分数保留的心力衰竭(HFpEF)是 发病率和死亡率的重要和非传递性原因，但有效治疗很少 战略。增加对HFpEF的了解已被指定为NIH的研究重点。 在心脏代谢性HFpEF患者中，常见的两个危险因素是肥胖和高血压。 两者都独立地与炎症和DD有关。炎症的程度是一个 可能导致心肌纤维化程度和心肌应激的关键决定因素 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。在此背景下，炎性免疫代谢 信号与疾病的进展有关，但对信号转导与疾病进展的关系知之甚少。 免疫新陈代谢如何调节DD。对于髓系细胞尤其如此，尤其是 巨噬细胞，其中对DD的免疫代谢构象不是未知的就是模糊的。 我们的初步数据表明，在DD期间巨噬细胞中存在显著的线粒体应激。这是 将对基本细胞机制的更好的基本理解与 揭示潜在的新陈代谢治疗靶点。在我们的第一个实验目标中，我们将 检测髓系脂类和线粒体代谢途径之间的因果关系 实验性DD。AIM II将阐明细胞内源性免疫代谢巨噬细胞信号 在DD相关的病理过程中调节炎症加速通路的网络。 AIM III将检验髓系细胞的治疗原理和临床意义 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。综上所述，这些研究将对潜在的 DD的炎症机制和治疗免疫靶点及免疫代谢 发信号。

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.