权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Desmin cardiac myopathy: molecular pathogenesis and novel treatment concepts

结蛋白心肌病：分子发病机制和新的治疗理念

基本信息

批准号：
228076738
负责人：
Professor Dr. Christoph S. Clemen
金额：
--
依托单位：
Institut für Luft- und Raumfahrtmedizin
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/228076738?language=en
关键词：
Desmin cardiac myopathy molecular pathogenesis

项目摘要

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.

人类结蛋白基因的杂合和纯合突变会导致家族性和散发性心肌病和肌病。心脏受累常常导致进行性心力衰竭或心源性猝死。在我们以前的工作中，我们已经表征了人类R350P结蛋白错义突变的临床、肌病理学和分子后果，这是在德国最常见的导致结缔组织病的基因缺陷。我们成功地产生了杂合和纯合的R350P结蛋白敲入小鼠。首先，对这些动物的分析揭示了人类结蛋白心肌病的组织病理学、活体电生理和功能特征。除了对我们的R350P结蛋白敲入小鼠进行更详细的病理生理分析外，我们还将进一步研究另外两个结构域特异的人类结蛋白突变体(R16C，头部区域；K449T，尾部区域)通过腺相关病毒(AAV)载体进行心脏基因转移的病理影响。由于人类肺萎缩症尚无特效治疗方法，我们将评估新的治疗方法的治疗潜力。在第一步中，我们将检验该假说是否由aav介导的小分子热休克蛋白(αB晶体蛋白，hsp70)的过度表达在我们的肺结缔组织病小鼠模型中起到心脏保护作用。在第二步中，我们将研究热休克蛋白诱导药物(香叶基香叶内酯、芍药苷)对这些小鼠模型心肌细胞的保护作用。我们的工作将为结蛋白心肌病的分子发病机制提供更深入的见解，并评估新的治疗概念的基础。