The role of Neurofibromin 2 in heart failure

项目摘要 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的心脏病。 缺乏、有毒代谢物的产生和氧化还原失衡，其驱动心力衰竭的发病机制。 然而，目前的心力衰竭疗法没有解决这个根本问题， 临床需要有效的机制为基础的治疗。改变的转录程序被认为 导致线粒体氧化磷酸化受损和能量产生不足， 心衰雌激素相关受体（ERRa、B和g）是线粒体呼吸的关键调节因子 在衰竭的心脏中下调，但调节其表达和活性的分子机制 仍然在很大程度上未知。在初步研究中，我们已经确定了一种新的分子途径， ERRb和ERRg在心肌细胞中的表达，并定义了一个新的心力衰竭途径， 线粒体氧化呼吸受损我们意想不到的结果表明 抑制蛋白神经纤维蛋白2（NF 2）促进适当代谢功能，且NF 2的心脏缺失 易使心脏响应于LV压力超负荷应激而发生病理性重构和衰竭。 心脏缺陷型NF 2 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Zscan 21作为NF 2的相互作用伴侣和一种新的代谢基因正调控因子 表达和心肌细胞线粒体氧化呼吸。因此，我们假设， 内源性NF 2与转录因子Zscan 21结合，正向调节ERRb的表达 和ERRg，并在心脏压力超负荷应激期间促进能量产生。的目标 目前的应用是进一步确定该途径的临床作用，并阐明其分子机制。 NF 2调节心肌ERRb和ERRg表达并防止能量缺乏的机制。 这些目标将在三个目标中实现。在目标1中，我们将建立证据的NF 2作为一个重要的， 在压力的初始和晚期阶段心脏代谢偶联和能量产生的新介质 过载应力在Aim 2中，我们将详细研究NF 2和Zscan 21之间的分子相互作用， 确定Zscan 21调节ERRb和ERRg表达、线粒体氧化呼吸的能力， 和心肌细胞的能量产生。在目标3中，我们将确定正常化的治疗潜力。 心脏NF 2用于HFrEF的压力超负荷模型中的治疗。该项目的长期目标是 定义心力衰竭中介导线粒体代谢功能障碍的机制事件， 新的治疗策略的候选人针对心力衰竭的早期阶段。

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.