Characterization of the FHL protein family in striated muscle

这项资助研究了一种叫做FHL蛋白的肌肉蛋白家族在骨骼肌和心肌中的作用。遗传性肌肉疾病，如肌肉萎缩症和肌病，可引起肌肉无力，这可能是严重的，并导致因呼吸肌肉衰竭而过早死亡，或在以后的生活中引起轻度无力。这些肌肉萎缩症中有缺陷的蛋白质是结构肌肉蛋白质，它连接并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，这是本次拨款申请的重点，与肌肉蛋白结合并可能调节肌肉蛋白，而肌肉蛋白已被证明会导致肌肉萎缩症和心肌病。检查这些相互作用将提供洞察这些肌肉疾病的生物学机制。此外，其中一种蛋白FHL1在肥厚性心肌病（心肌增厚）中显著升高，肥厚性心肌病是年轻人心源性猝死的主要原因。我们正在培育转基因小鼠，使其心肌中的FHL1蛋白水平增加，以确定增加的FHL1本身是否足以促进心肌增厚。这些研究应该会导致对心脏和骨骼肌疾病发展的进一步了解，这可能会导致未来新的治疗方法。

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.