Characterization of the FHL protein family in striated muscle

这项资助研究了一系列肌肉蛋白，称为FHL蛋白，在骨骼肌和心肌中的作用。遗传性肌肉疾病，如肌营养不良和肌病，会导致肌肉无力，这可能是严重的，并因呼吸肌衰竭而导致过早死亡，或在以后的生活中导致轻微的虚弱。在这些肌营养不良症中有缺陷的蛋白质是结构性肌肉蛋白质，它连接和稳定肌肉中的收缩纤维，保护肌肉免受反复肌肉收缩造成的压力和损伤。我们已经确定，FHL蛋白，这是这项赠款申请的重点，结合并潜在地调节肌肉蛋白，已被证明导致各种形式的肌肉营养不良和心肌病。对这些相互作用的研究将提供对这些肌肉疾病的生物学机制的见解。此外，其中一种蛋白质FHL1在肥厚性心肌病、心肌肥厚中显著增加，这是导致年轻人心脏性猝死的主要原因。我们正在创造转基因小鼠，使他们的心肌中FHL1蛋白水平增加，以确定增加的FHL1本身是否足以促进心肌肥厚。这些研究应该会进一步了解心脏和骨骼肌疾病的发展，这可能会在未来导致新的治疗方法。

This grant examines the role of a family of muscle proteins, called FHL proteins, in skeletal and heart muscle. Inherited muscular disorders such as muscular dystrophy and myopathies, cause muscle weakness, which may be profound and lead to premature death due to respiratory muscle failure, or cause mild weakness later in life. The proteins which are defective in these muscular dystrophies are structural muscle proteins, which link and stabilize the contractile fibres in muscle and protect the muscle from the stresses and damage resulting from repeated muscular contraction. We have identified that the FHL proteins, which are the focus of this grant application, bind to and potentially regulate muscle proteins, which have been shown to cause forms of muscular dystrophy and cardiomyopathy. Examination of these interactions will provide insights into the biological mechanism of these muscle disorders. Furthermore, one of these proteins, FHL1 is significantly increased in hypertrophic cardiomyopathy, heart muscle thickening, a major cause of sudden cardiac death in young adults. We are creating transgenic mice, which make increased levels of FHL1 protein in their heart muscle, to determine whether increased FHL1, by itself is sufficient to promote heart muscle thickening. These studies should lead to further understanding of the development of diseases of heart and skeletal muscle, which may lead to novel treatments in the future.