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)。虽然有许多治疗方法可用，但心力衰竭的预防和治疗仍然是主要的临床问题。心脏重构，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一项重大改进，在加入之前优化的治疗方法后，死亡率降低了30%。这些有益的作用使盐皮质激素受体(MR)和醛固酮被认为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被改变，特别是在MR和其他髓系修饰剂的作用下。我们最近的数据显示，髓系细胞中的MR可以起到“髓系修饰物”的作用，改变髓系细胞的表型。髓系MR在血管紧张素II引起的心脏炎症、肥大和纤维化反应中具有重要作用。通过了解MR在这些髓系细胞中的作用以及髓系MR基因敲除中改变的髓系表型是如何有益的，我们将能够确定其机制，然后能够操纵这些髓系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)在心脏重构的生理学和遗传学模型中通过MR失活来确定心脏重构的病理生理学变化。这些研究将包括疾病模型的进展和功能评估。生理学相关模型包括心肌梗死模型、慢性高血压模型和肥厚型心肌病遗传模型；2)定义免疫髓系细胞在重塑过程中的变化及其如何参与重塑机制。这还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髓系表型。3)基于其他髓系修饰物改变炎症表型的能力，验证这一假设，即其他髓系修饰物可以以预期的方式改变重塑，从而支持这些细胞的作用，并可能为治疗干预指明方向。

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.