THE ROLES OF CYTOSKELETAL PROTEINS IN SKELETAL MUSCLE FUNCTION AND DISEASE

先天性肌病是骨骼肌的遗传性疾病，通常在出生时或幼儿期出现，其特征是肌张力差和肌无力。这组疾病包括线状体肌病、中央核疾病、先天性纤维类型不称和肌管性肌病。所有这些疾病的特征是肌节的解体，肌节是骨骼肌细胞内参与收缩的主要结构。在线虫性肌病患者中，已发现编码肌节丝状系统蛋白质的五个基因发生突变。因此，其他细丝、粗丝和Z线蛋白的基因是这些疾病的极好候选者。我们实验室的研究已经确定了肌节的一个新区域，编码该区域中存在的蛋白质的基因为先天性肌病提供了额外的候选者。我们将进一步研究这种新结构中的蛋白质，以确定其功能及其在肌肉疾病病理学中的作用。为了研究疾病的病理和肌肉无力之间的关系，在线虫性肌病，我们产生了一个小鼠模型，通过表达突变蛋白，α-原肌球蛋白慢，发现在人类患者的小鼠。在人类中发现的疾病的所有特征都存在于小鼠中。这种疾病在小鼠中的一个关键特征是肌肉细胞直径增长或肥大以抵消肌肉无力的能力。我们将使用这些小鼠来试验包括肥大诱导剂在内的治疗方法，以预防和逆转肌肉无力。此外，我们将产生一个额外的小鼠模型，这种疾病与突变的基因编码另一种丝状蛋白。使用微阵列分析比较两种模型将有助于我们识别在这种疾病中受到影响的其他基因，并生成有助于诊断这种疾病的分子表达谱。

Congenital myopathies are inherited diseases of skeletal muscle that typically present at birth or in early chilhood and are characterised by poor muscle tone and muscle weakness. This group of disorders includes nemaline myopathy, central core disease, congenital fiber type disproportion, and myotubular myopathy. All of these disorders are characterised by disorganisation of the sarcomere, the major structure within skeletal muscle cells that is involved in contraction. In nemaline myopathy patients, mutations have been found in five genes that encode proteins of the filamentous systems of the sarcomere. Therefore, the genes for other thin filament, thick filament and Z-line proteins are excellent candidates for these disorders. Research from our lab has identified a novel region of the sarcomere and the genes encoding the proteins present in this region provide additional candidates for the congenital myopathies. We will further characterise the proteins in this novel structure to determine its function and the role that it plays in muscle disease pathologies. In order to study the relationship between disease pathology and muscle weakness in nemaline myopathy, we generated a mouse model by expressing a mutant protein, a-tropomyosin slow, found in human patients in mice. All features of the disease found in humans are present in the mice. A key feature of this disease in mice is the ability for muscle cells to grow in diameter or hypertrophy to offset the muscle weakness. We will use these mice to trial therapies including hypertropy-inducing agents, to prevent and reverse muscle weakness. In addition, we will generate an additional mouse model for this disease with a mutation in a gene encoding another filamentous protein. A comparison of the two models using microarray analysis will help us identify additional genes that are being affected in this disease and to generate a molecular expression profile that will aid in the diagnosis of this disease.