Myeloid Reprogramming in Cardiac Protection by Aldosterone Antagonists

描述（由申请人提供）：心力衰竭是美国发病率和死亡率的主要原因，每年约有570万人受到影响，导致30万人死亡（NHLBI统计数据）。虽然有许多可用的治疗方法，预防和治疗心力衰竭仍然是主要的临床问题。心脏重塑，包括心肌细胞肥大、纤维化反应和功能改变，可能是导致心力衰竭的有害病理过程。醛固酮拮抗剂是心力衰竭治疗的主要改进，当添加到先前优化的治疗中时，死亡率降低30%。这些有益的作用使得人们认识到矿化皮质激素受体（MR）和醛固酮是主要的独立心血管疾病介质。我们的长期目标是了解炎症过程和免疫细胞亚型如何参与心脏重塑，以及这些过程如何在治疗上特别是通过MR和其他髓细胞调节剂改变。我们最近的数据表明，髓细胞中的MR可以作为“髓细胞修饰剂”改变髓细胞的表型。髓系磁共振在血管紧张素II对心脏的炎症、肥厚和纤维化反应中起关键作用。通过了解MR在这些髓细胞中的作用，以及髓细胞MR敲除中改变的髓细胞表型是如何有益的，我们将能够确定其机制，然后能够操纵这些髓细胞以获得进一步的治疗益处。为了实现这些目标，我们将1)在心脏重构的生理和遗传模型中通过MR失活来确定心脏重构病理生理的精确改变。这些研究将包括疾病模型的进展和功能评估。生理相关模型包括心肌梗死（LAD结扎）、慢性高血压（主动脉束带）和肥厚性心肌病的遗传模型，2)定义了免疫髓细胞在重塑过程中的改变及其参与重塑的机制。这也将涉及进一步测试目标免疫细胞类型和通过基因操作改变骨髓表型。3)验证其他髓系修饰剂可以基于其改变炎症表型的能力以预测的方式改变重塑的假设，从而支持这些细胞的作用，并潜在地指出治疗干预的目标。

DESCRIPTION (provided by applicant): Cardiac failure is a major cause of morbidity and mortality in the US with about 5.7 million affected and resulting in 300,000 deaths each year (NHLBI statistics). Although there are a number of treatments available, prevention and treatment of heart failure remain major clinical problems. Cardiac remodeling, which includes cardiomyocyte hypertrophy, fibrotic responses and changes in function, can be a detrimental pathologic process that leads to cardiac failure. Aldosterone antagonists are a major improvement in heart failure treatment that results in 30% decrease in mortality when added to previously optimized therapy. These beneficial effects have led to recognition of the mineralocorticoid receptor (MR) and aldosterone as major independent cardiovascular disease mediator. Our long-term goal is to understand how inflammatory processes and immune cells subtypes participate in cardiac remodeling and how these processes can be altered therapeutically particularly by MR and other myeloid modifiers. Our recent data show that MR in myeloid cells can act as a "Myeloid Modifier" altering the phenotype of myeloid cells. Myeloid MR has a critical function in the cardiac inflammatory, hypertrophic and fibrotic response in response to angiotensin II. By understanding the role of MR in these myeloid cells and how the altered myeloid phenotype in myeloid MR knockouts is beneficial, we will be able to define the mechanisms and then be able to manipulate these myeloid cells for further therapeutic benefit. To accomplish these goals, we will 1) determine the precise alterations in the pathophysiology of cardiac remodeling by MR inactivation in physiologic and genetic models of cardiac remodeling. These studies will include the progression and functional evaluation of the disease models. Physiological relevant models include a model for MI (LAD ligation), chronic hypertension (aortic banding), and a genetic model of hypertrophic cardiomyopathy, 2) define the alteration in immune myeloid cells during the remodeling and how they participate in the mechanisms of remodeling. This will also involve further testing of the target immune cell type and alteration of the myeloid phenotype by genetic manipulation. 3) test the hypothesis that other myeloid modifiers can alter remodeling in predicted ways based on their ability to alter the inflammatory phenotypes thus supporting the role of these cells and potentially pointing the way to targets for therapeutic intervention.