The role of the z-disc protein LMCD1 in cardiac remodeling.

z 盘蛋白 LMCD1 在心脏重塑中的作用。

• 批准号: 467267736
• 负责人: Professor Dr. Derk Frank
• 金额: --
• 依托单位: Klinik für Innere Medizin III: Schwerpunkte Kardiologie, Angiologie und internistische Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/467267736?language=en
• 关键词: role; disc; protein; LMCD1; cardiac

Cardiac hypertrophy is an integral part of the remodeling process the heart undergoes when subjected to biomechanical or neurohumoral stressors. Adaptive hypertrophy is typically a short-term and mostly reversible compensation to maintain cardiac function. However, when stressors persist, the hypertrophy might become maladaptive or pathological. On the cellular level, the development of pathological hypertrophy is hallmarked not only by cardiomyocyte growth but also by fibrosis, and apoptotic cell death. Typical stimuli of maladaptive remodeling are a prior myocardial infarction, hypertension, valvular heart disease, and certain mutations in cardiac proteins. Several signaling cascades are involved in these processes. The transition between adaptive and maladaptive hypertrophy and the signaling involved might be indistinct in some cases. Yet, in the context of pathological remodeling, the NFAT/calcineurin signaling pathway plays an important role. Main goal of the project is the in-depth in vivo characterization of the role of the protein LMCD1 in cardiac remodeling. In previous studies we could showthat LMCD1 is sufficient to induce Calcineurin-mediated cardiac hypertrophy in vivo. The focus now will be on the analyses of the effects of the downregulation of LMCD1 in vitro and in vivo. To pursue this task, we have newly generated a conditional LMCD1-“knockout”-mouse model. The following hypotheses will be addressed: a) Does the downregulation of LMCD1 affect the calcineurin-mediated hypertrophy in biomechanically stretched cardiomyocytes in vitro? b) Does the downregulation of LCMD1 in vivo beneficially modulate pathological hypertrophy induced by pressure overload or neurohumoral activation? Here, we will also utilize a strategy for an LMCD1 knockdown after the onset of the hypertrophic stimulus to test for potential therapeutic effects. c) Identification and characterization of mechanistically relevant novel players (genes/transcripts/non-coding RNAs) which play role in cardiac remodeling, in particular in the context of the LMCD1 “knockout”. We are also planning to include human blood samples from patients with severe symptomatic aortic stenosis in these analyses in order to identify circulating non-coding RNAs which might play a critical role in the mediation of pathological hypertrophy. These results might help not only to understand the mechanistic background of LMCD1 but may also to improve our in-depth understanding of maladaptive remodeling in general and trigger future experiments. Taken together, we are expecting to a identify a potentially prophylactic or even therapeutic effect for the downregulation of LMCD1 in vivo. Ultimately, these findings could lead to further translation towards a treatment for the negative effects of maladaptive remodeling.

心脏肥大是心脏在受到生物力学或神经体液应激时经历的重塑过程的组成部分。适应性肥大通常是一种短期且大部分可逆的补偿，以维持心脏功能。然而，当应激源持续存在时，肥大可能变得适应不良或病理性。在细胞水平上，病理性肥大的发展不仅以心肌细胞生长为标志，而且还以纤维化和凋亡性细胞死亡为标志。适应不良重构的典型刺激是先前的心肌梗死、高血压、心脏瓣膜病和心脏蛋白的某些突变。在这些过程中涉及几个信号级联。在某些情况下，适应性肥大和适应不良肥大之间的转变以及所涉及的信号转导可能是不清楚的。然而，在病理性重塑的背景下，NFAT/钙调神经磷酸酶信号通路起着重要的作用。该项目的主要目标是深入研究LMCD1蛋白在心脏重塑中的作用。在以前的研究中，我们可以证明LMCD 1足以在体内诱导钙调神经磷酸酶介导的心脏肥大。现在的重点将是在体外和体内的LMCD 1下调的影响的分析。为了完成这项任务，我们新产生了一个条件性LMCD 1-"敲除"-小鼠模型。以下假设将得到解决：a）LMCD 1的下调是否影响钙调神经磷酸酶介导的体外生物力学拉伸心肌细胞肥大？B）体内LCMD 1的下调是否有益地调节由压力超负荷或神经体液激活诱导的病理性肥大？在这里，我们还将利用肥大刺激开始后LMCD1敲低的策略来测试潜在的治疗效果。c）鉴定和表征在心脏重塑中起作用的机械相关的新参与者（基因/转录物/非编码RNA），特别是在LMCD 1 "敲除"的背景下。我们还计划在这些分析中纳入来自严重症状性主动脉瓣狭窄患者的人血液样本，以鉴定可能在病理性肥大介导中发挥关键作用的循环非编码RNA。这些结果可能不仅有助于理解LMCD 1的机制背景，而且还可能提高我们对适应不良重塑的深入理解，并引发未来的实验。综上所述，我们期望确定LMCD 1在体内下调的潜在预防甚至治疗作用。最终，这些发现可能会导致进一步翻译为适应不良重塑的负面影响的治疗。