Myeloid Reprogramming in Cardiac Protection by Aldosterone Antagonists

醛固酮拮抗剂在心脏保护中的骨髓重编程

• 批准号: 9338941
• 负责人: RICHARD M MORTENSEN
• 金额: $ 8.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338941
• 关键词: Ablation; Acute; Affect; Aldosterone; Aldosterone Antagonists; Angiotensin II; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antihypertensive Agents; Area; Back; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cell Count; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Data; Dendritic Cells; Disease Progression; Disease model; Diuretics; Evaluation; Experimental Models; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic Models; Goals; Heart; Heart Hypertrophy; Heart failure; Hormonal; Human; Hypertension; Hypertrophic Cardiomyopathy; Hypertrophy; ITGAX gene; Immune; Immune Targeting; Inflammation; Inflammatory; Injury; Interleukin 4 Receptor; Investigation; Kinetics; Knock-out; Lead; Ligation; Mediating; Mediator of activation protein; Mineralocorticoid Receptor; Modeling; Modification; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; NG-Nitroarginine Methyl Ester; National Heart, Lung, and Blood Institute; PPAR gamma; Participant; Pathologic; Pathologic Processes; Pathway interactions; Phase; Phenotype; Physiological; Play; Population; Prevention; Process; Production; Publications; Research; Role; Signal Transduction; Stimulus; System; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment Failure; base; cell type; coronary fibrosis; cytokine; deep sequencing; diphtheria toxin receptor; feeding; fetal; genetic manipulation; healing; homologous recombination; in vivo; macrophage; monocyte; mortality; novel strategies; physiologic model; pressure; programs; public health relevance; response; secondary analysis; statistics; targeted treatment; therapeutic target; trafficking; transcriptome; transcriptome sequencing

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.

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570万人受累，导致30万人死亡（NHLBI统计数据）。虽然有许多可用的治疗方法，但心力衰竭的预防和治疗仍然是主要的临床问题。心脏重塑是导致心力衰竭的一种有害的病理过程，包括心肌细胞肥大、纤维化反应和功能改变。 醛固酮拮抗剂是心力衰竭治疗的一项重大改进，当添加到先前优化的治疗中时，死亡率降低30%。这些有益的作用导致盐皮质激素受体（MR）和醛固酮作为主要的独立的心血管疾病介质的认识。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改变，特别是通过MR和其他骨髓修饰剂。 我们最近的数据表明，髓系细胞中的MR可以作为“髓系修饰剂”改变髓系细胞的表型。髓样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关键作用。通过了解MR在这些骨髓细胞中的作用以及骨髓MR敲除中改变的骨髓表型如何有益，我们将能够定义机制，然后能够操纵这些骨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）在心脏重塑的生理和遗传模型中，通过MR失活确定心脏重塑病理生理学的精确改变。这些研究将包括疾病模型的进展和功能评价。生理学相关模型包括MI（LAD结扎）模型、慢性高血压（主动脉结扎）模型和肥厚型心肌病的遗传模型，2）定义重塑期间免疫髓样细胞的改变以及它们如何参与重塑机制。这还将涉及进一步测试靶免疫细胞类型和通过遗传操作改变骨髓表型。3)测试假设，即其他骨髓修饰剂可以基于其改变炎性表型的能力以预测的方式改变重塑，从而支持这些细胞的作用，并可能为治疗干预的靶点指明方向。