Desmin cardiac myopathy: molecular pathogenesis and novel treatment concepts

人类desmin基因的杂合子和纯合子突变引起家族性和散发性心肌病和肌病。心脏受累常导致进行性心力衰竭或心源性猝死。在我们之前的工作中，我们已经描述了人类R350P消丝蛋白错义突变的临床、肌肉病理学和分子后果，这是德国最常见的导致消丝蛋白病的基因缺陷。我们成功培育了杂合和纯合的R350P蛋白敲入小鼠。首先对这些动物进行分析，揭示了人类desmin心肌病的组织病理学、体内电生理和功能特征。除了对R350P片段蛋白敲入小鼠进行更详细的病理生理分析外，我们还将利用腺相关病毒（AAV）载体进行心脏基因转移，进一步研究另外两个区域特异性人类片段蛋白突变体（R16C，头部区域；K449T，尾部区域）的病理影响。由于没有针对人类末梢病变的特异性治疗方法，我们将评估新的治疗方法的治疗潜力。在第一步，我们将验证aav介导的小热休克蛋白（αBcrystallin, Hsp70）的过表达是否在我们的神经病变小鼠模型中发挥心脏保护作用。第二步，我们将研究热休克蛋白诱导药物（香叶酮、芍药苷）对小鼠心肌细胞的保护作用。我们的工作将为desmin心肌病的分子发病机制提供更深入的见解，并评估新的治疗理念的基础。

Heterozygous and homozygous mutations of the human desmin gene cause familial and sporadic cardiomyopathies and myopathies. Cardiac involvement frequently leads to progressive heart failure or sudden cardiac death. In our previous work we have characterized the clinical, myopathological, and molecular consequences of a human R350P desmin missense mutation, which is the most frequently encountered gene defect causing desminopathies in Germany.We have successfully generated heterozygous and homozygous R350P desmin knock-in mice. First analyses of these animals revealed histopathological, in vivo electrophysiological and functional characteristics of the human desmin cardiomyopathy. In addition to a more detailed pathophysiological analysis of our R350P desmin knock-in mice, we will further study the pathological impact of two further domain-specific human desmin mutants (R16C, head domain; K449T, tail domain) using cardiac gene transfer with adeno-associated virus (AAV) vectors. Since no specific therapy is available for human desminopathies, we will evaluate the therapeutic potential of novel therapeutic approaches. In a first step, we will test the hypothesis if the AAV-mediated over-expression of small heat shock proteins (αBcrystallin, Hsp70) exert a cardio-protective effect in our desminopathy mouse models. In a second step, we will address the cell protective effect of heat shock protein inducing drugs (geranylgeranylacetone, paeoniflorin) on cardiomyocytes from these mouse models. Our work shall provide deeper insights into the molecular pathogenesis of desmin cardiomyopathies and evaluate the basis for novel treatment concepts.