The role of Neurofibromin 2 in heart failure

神经纤维蛋白 2 在心力衰竭中的作用

• 批准号: 10446037
• 负责人: Dominic P Del Re
• 金额: $ 58.18万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10446037
• 关键词: Acute; Affect; Binding; Biopsy; Cardiac; Cardiac Myocytes; Chronic; Chronic stress; Clinical; Coupling; Data; Disease; Disease Progression; Down-Regulation; Economic Burden; Evaluation; Event; Failure; Gene Expression; Generations; Genes; Genetic Transcription; Heart; Heart failure; Homeostasis; Human; Impairment; Intervention; Lead; Link; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Mus; Myocardial; Myocardial dysfunction; Neuraxis; Neurofibromatosis 2; Neurofibromin 2; Organ; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Pathogenesis; Pathologic; Pathway interactions; Phase; Production; Proteomics; Respiration; Role; Scaffolding Protein; Signal Pathway; Stress; Testing; Therapeutic; Transcriptional Regulation; Tumor Suppressor Proteins; Wild Type Mouse; base; cardiogenesis; cell growth; estrogen-related receptor; experimental study; flexibility; genome-wide; global health; improved; in vivo; loss of function mutation; novel; novel therapeutic intervention; novel therapeutics; pressure; prevent; programs; response; therapeutic candidate; transcription factor; transcriptome

Project Summary The heart is a metabolically demanding organ, and derangements in metabolic processes lead to energetic deficits, generation of toxic metabolites, and redox imbalance, which drive pathogenesis to heart failure. However, current therapies for heart failure do not address this fundamental issue, and there remains an unmet clinical need for effective mechanism-based treatments. Altered transcriptional programs are thought to contribute significantly to impaired mitochondrial oxidative phosphorylation and insufficient energy production in heart failure. The estrogen-related receptors (ERRa, b, and g) are key regulators of mitochondrial respiration that are downregulated in the failing heart, yet the molecular mechanisms regulating their expression and activity remain largely unknown. In preliminary studies we have identified a novel molecular pathway that promotes the expression of ERRb, and ERRg in cardiomyocytes, and define a new heart failure pathway linking chronic stress to impairment of mitochondrial oxidative respiration. Our unexpected results demonstrate that the tumor suppressor protein Neurofibromin 2 (NF2) promotes proper metabolic function, and that cardiac deletion of NF2 predisposes the heart to pathological remodeling and failure in response to LV pressure overload stress. Transcriptome profiling of cardiac deficient NF2 cKO hearts indicated downregulation of metabolic pathways and decreased expression/activity of ERRb and ERRg. Using a proteomics-based approach, we identified the transcription factor Zscan21 as an interacting partner of NF2 and a novel positive regulator of metabolic gene expression and mitochondrial oxidative respiration in cardiomyocytes. Therefore, we hypothesize that endogenous NF2 engages the transcription factor Zscan21 to positively regulate expression of ERRb and ERRg and promote energy production during pressure overload stress in the heart. The objectives of the current application are to further define the clinical role of this pathway, and to elucidate the molecular mechanisms by which NF2 regulates expression of myocardial ERRb and ERRg and prevents energy deficit. These objectives will be accomplished in 3 aims. In Aim1, we will establish evidence of NF2 as an important and novel mediator of cardiac metabolic coupling and energy production during the initial and late phases of pressure overload stress. In Aim2, we will investigate in detail the molecular interaction between NF2 and Zscan21 and determine the ability of Zscan21 to regulate expression of ERRb and ERRg, mitochondrial oxidative respiration, and energy production in cardiomyocytes. In Aim3, we will determine the therapeutic potential of normalizing cardiac NF2 for treatment in the pressure overload model of HFrEF. The long-term objective of this project is to define mechanistic events that mediate mitochondrial metabolic dysfunction in heart failure and identify potential candidates for new therapeutic strategies targeting early stages of heart failure.

项目概要 心脏是一个代谢要求很高的器官，代谢过程的紊乱会导致精力充沛 缺陷、有毒代谢物的产生和氧化还原失衡，这些都会导致心力衰竭的发病机制。 然而，目前心力衰竭的治疗方法并没有解决这个根本问题，仍然有一个未得到满足的问题 临床需要有效的基于机制的治疗。改变转录程序被认为 严重影响线粒体氧化磷酸化和能量产生不足 心脏衰竭。雌激素相关受体（ERRa、b 和 g）是线粒体呼吸的关键调节因子 在衰竭心脏中下调，但调节其表达和活性的分子机制 仍然很大程度上不为人所知。在初步研究中，我们发现了一种新的分子途径，可以促进 心肌细胞中 ERRb 和 ERRg 的表达，并定义了与慢性应激相关的新心力衰竭途径 线粒体氧化呼吸受损。我们意想不到的结果表明，肿瘤 抑制蛋白神经纤维蛋白 2 (NF2) 促进正常的代谢功能，并且 NF2 的心脏缺失 导致心脏因左心室压力超负荷应激而发生病理性重塑和衰竭。 心脏缺陷 NF2 cKO 心脏的转录组分析表明代谢途径下调 ERRb 和 ERRg 的表达/活性降低。使用基于蛋白质组学的方法，我们确定了 转录因子 Zscan21 作为 NF2 的相互作用伙伴和代谢基因的新型正调节因子 心肌细胞中的表达和线粒体氧化呼吸。因此，我们假设 内源性 NF2 结合转录因子 Zscan21 正向调节 ERRb 的表达 和 ERRg 并促进心脏压力超负荷期间的能量产生。的目标 目前的应用是进一步明确该途径的临床作用，并阐明其分子机制 NF2 调节心肌 ERRb 和 ERRg 表达并防止能量缺乏的机制。 这些目标将通过三个目标来实现。在目标 1 中，我们将建立 NF2 作为重要且重要的疾病的证据。 压力初始和晚期阶段心脏代谢耦合和能量产生的新型介质 过载压力。在 Aim2 中，我们将详细研究 NF2 和 Zscan21 之间的分子相互作用， 确定 Zscan21 调节 ERRb 和 ERRg 表达、线粒体氧化呼吸、 和心肌细胞的能量产生。在 Aim3 中，我们将确定正常化的治疗潜力 心脏 NF2 用于治疗 HFrEF 压力超负荷模型。该项目的长期目标是 定义介导心力衰竭线粒体代谢功能障碍的机制事件并确定潜在的 针对心力衰竭早期阶段的新治疗策略的候选者。