MDM2-HIF signaling in pathological ventricular remodeling

病理性心室重构中的 MDM2-HIF 信号传导

• 批准号: 10705352
• 负责人: Jason Becker
• 金额: $ 59.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705352
• 关键词: Adult; Angiogenic Proteins; Binding Proteins; Blood capillaries; Cardiac Myocytes; Cardiac Myosins; Cardiomyopathies; Cause of Death; Cell Cycle; Cell Respiration; Cell division; Cells; DNA Damage; DNA biosynthesis; Data; Development; Diastolic heart failure; Disease; Equilibrium; Fatty Acids; Genetic; Genetic Diseases; Genetic Models; Glucose; Goals; Growth; HIF1A gene; Heart; Heart failure; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Lead; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Metabolic; Metabolism; Microvascular Dysfunction; Modeling; Molecular; Mus; Myocardial; Myocardial dysfunction; Myosin ATPase; Pathologic; Pathway interactions; Patients; Phase; Play; Population; Production; Proteins; Regulation; Role; Sarcomeres; Secondary to; Signal Pathway; Signal Transduction; Testing; Tissues; Ventricular Remodeling; density; experimental study; heart metabolism; hypoxia inducible factor 1; in vivo; innovation; mortality; mouse model; mutant; non-genetic; novel; novel therapeutics; pressure; prevent; replication stress; response; sarcomeric cardiomyopathy

Project Summary: Multiple acquired and genetic conditions can lead to pathological left ventricular hypertrophy (LVH). Importantly, it has been recognized for over 50 years that pathological LVH is associated with heart failure and increased mortality in the human population. In addition, LVH is strongly associated with both heart failure with preserved systolic function (HFpEF) and heart failure with reduced systolic function (HFrEF). At the tissue level, the primary cause of LVH is cardiomyocyte hypertrophy and there are a multitude of intracellular signaling pathways involved in hypertrophic cardiomyocyte growth. However, non-cardiomyocyte myocardial cell populations also contribute to the pathological remodeling in LVH and the downstream sequelae of this condition. For example, in many forms of human cardiomyopathy there are reductions in myocardial capillary density which is thought to contribute to myocardial dysfunction in these diseases. Therefore, it is not only critical to understand the primary causes of pathological cardiomyocyte growth but also how the myocardial microenvironment responds to these changes. To uncover the mechanisms regulating LVH and pathological remodeling in the mammalian heart, we utilized murine models that allow manipulation of the sarcomere protein, cardiac myosin binding protein 3 (MYBPC3). We discovered that loss of MYBPC3 protein causes rapid changes in cardiomyocyte growth through dysregulated cell cycle pathways causing cardiomyocyte endoreplication (DNA replication without cell division). We then determined that the dysregulated cardiomyocyte DNA synthesis in sarcomeric cardiomyopathy leads to replication stress induced DNA damage in cardiomyocytes and activation of DNA damage response (DDR) pathways. We have now identified that the DDR effector protein, murine double mutant 2 (MDM2), plays a crucial role in pathological left ventricular remodeling in both genetic and acquired forms of left ventricular hypertrophy. We hypothesize that dynamic changes in MDM2 and HIF signaling accelerate pathological hypertrophic remodeling by altering both the myocardial microvasculature and cardiac metabolism. To test this hypothesis, we will pursue the following aims: Aim 1: Define the role of MDM2 and the HIF switch in altering the myocardial microvasculature in genetic forms of LVH. Aim 2: Determine if MDM2 and the HIF switch alters cardiomyocyte metabolism in genetic forms of LVH. Aim 3: Define which components of cardiomyocyte MDM2-HIF signaling are regulating pathological LV remodeling in acquired forms of LVH. At the conclusion of these innovative and high impact studies, we will have defined a novel role for MDM2-HIF signaling during key periods of pathological left ventricular hypertrophy secondary to both genetic and acquired causes. Through selective modulation of key components of this pathway our goal is to disrupt key maladaptive myocardial remodeling responses and uncover novel therapeutic opportunities for both genetic and non-genetic forms of human cardiomyopathy.

项目概要： 多种获得性和遗传性疾病可导致病理性左心室肥大（LVH）。 重要的是，50多年来已经认识到病理性LVH与心力衰竭相关， 增加了人类的死亡率。此外，LVH与心力衰竭和 收缩功能保留（HFpEF）和心力衰竭伴收缩功能降低（HFrEF）。在组织 在水平上，LVH的主要原因是心肌细胞肥大， 参与肥大心肌细胞生长的信号通路。然而，非心肌细胞心肌 细胞群也有助于LVH的病理性重塑及其下游后遗症， 条件例如，在许多形式的人类心肌病中， 密度，这被认为有助于这些疾病中的心肌功能障碍。因此，它不仅 关键是要了解病理性心肌细胞生长的主要原因， 微环境对这些变化的反应。为了揭示LVH的调节机制和病理机制， 在哺乳动物心脏重塑中，我们利用了允许操纵肌节的小鼠模型， 心肌肌球蛋白结合蛋白3（MYBPC 3）。我们发现，MYBPC 3蛋白的缺失会导致快速的 通过失调的细胞周期途径引起心肌细胞生长的变化 核内复制（没有细胞分裂的DNA复制）。然后我们确定， 肌节型心肌病中心肌细胞DNA合成导致复制应激诱导的DNA损伤 在心肌细胞和DNA损伤反应（DDR）途径的激活。我们现在已经确定， DDR效应蛋白，小鼠双突变体2（MDM 2），在病理性左心室 在遗传和获得性左心室肥大的重塑。我们假设， MDM 2和HIF信号的改变通过改变细胞内的蛋白质， 心肌微血管和心脏代谢。为了验证这一假设，我们将进行以下研究： 目的：目的1：明确MDM 2和HIF开关在改变心肌微血管中的作用， LVH的形式。目的2：确定MDM 2和HIF开关是否以遗传形式改变心肌细胞代谢 的LVH。目的3：确定心肌细胞MDM 2-HIF信号的哪些组分调节病理性LV 获得性LVH的重塑。在完成这些创新和高影响力的研究后，我们将 已经确定了MDM 2-HIF信号在病理性左心室肥厚的关键时期的新作用， 继发于遗传和后天原因的肥大。通过选择性调制关键组件 我们的目标是破坏关键的适应不良心肌重塑反应， 为人类心肌病的遗传和非遗传形式提供治疗机会。