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

心脏肥大是心脏在受到生物力学或神经体液应激时所经历的重塑过程的一个组成部分。适应性肥厚通常是维持心功能的一种短期且大部分可逆的补偿。然而，当压力源持续存在时，肥大可能会变得不适应或病态。在细胞水平上，病理性肥大的发展不仅以心肌细胞生长为特征，还以纤维化和凋亡细胞死亡为特征。适应性重构不良的典型刺激因素是既往心肌梗死、高血压、瓣膜性心脏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，适应性肥大和非适应性肥大之间的转变及其所涉及的信号可能是不明确的。然而，在病理性重构的背景下，NFAT/钙调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体内表征LMCD1蛋白在心脏重塑中的作用。在以往的研究中，我们可以证明LMCD1足以在体内诱导钙调磷酸酶介导的心肌肥厚。现在的重点是分析LMCD1下调在体外和体内的影响。为了完成这项任务，我们新生成了一个条件LMCD1“敲除”小鼠模型。本文将讨论以下假设：a) LMCD1的下调是否影响体外生物力学拉伸心肌细胞中钙调磷酸酶介导的肥大？b)体内LCMD1的下调是否有利于调节压力过载或神经体液激活引起的病理性肥大？在这里，我们还将利用在肥厚性刺激开始后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构中起作用的机制相关的新参与者（基因/转录物/非编码rna），特别是在LMCD1“敲除”的背景下。我们还计划在这些分析中纳入严重症状性主动脉狭窄患者的人类血液样本，以确定循环非编码rna可能在病理肥厚的介导中发挥关键作用。这些结果可能不仅有助于了解LMCD1的机制背景，而且可能有助于我们深入了解一般的适应不良重塑，并引发未来的实验。综上所述，我们期望在体内发现一种潜在的预防甚至治疗LMCD1下调的作用。最终，这些发现可能导致进一步转化为治疗不适应重塑的负面影响。

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.