Titin in vascular smooth muscle – from scaffold to mechanosensor

肌凝蛋白是横纹肌的主要收缩单位肌节内的一种巨蛋白。它决定了心脏和骨骼肌的弹性。因此，titin突变经常引起心脏或骨骼肌疾病，这与它在生物力学、生长和代谢中的作用有关。平滑肌细胞表达titin的水平要低得多，直到最近，关于其在缺乏经典肌节的肌肉细胞中的潜在功能的信息很少。在我们发现平滑肌titin在子宫中与蠕动和正确植入有关的作用后，我们现在将我们的分析扩展到血管平滑肌。在主动脉中，我们发现截断的titin亚型和全长的titin亚型。我们的初步研究表明，titin在主动脉和小动脉中具有不同的收缩和弹性功能。在这里，我们将研究平滑肌titin的生物力学，以及它在塑造血压曲线、机械转导和与代谢的联系中的作用。此外，我们将在mRNA和蛋白质水平上剖析titin亚型的表达，以及解决表型的分子基础。这包括使用定位蛋白质组学作为一种公正的方法来表征平滑肌titin的蛋白质环境。提出的工作对由titin突变导致血管表型的心肌病患者的护理具有启示意义。

Titin is a giant protein within the sarcomere – the main contractile unit of striated muscle. It determines the elastic properties of heart and skeletal muscle. Thus, titin mutations frequently cause heart or skeletal muscle disease that relate to its role in biomechanics, growth and metabolism.Smooth muscle cells express titin at much lower levels and until recently, there was little information on its potential functions in muscle cells that lack classical sarcomeres. After we have uncovered a role of smooth muscle titin in the uterus that relates to peristalsis and proper implantation, we have now extended our analysis to vascular smooth muscle. In the aorta, we find a truncated titin isoform as well as full-length titin. Our preliminary suggest differential contractile and elastic functions of titin in aorta versus smaller arteries.Here we will study the biomechanics of smooth muscle titin as well as its role in shaping the blood pressure curve, mechanotransduction and links to metabolism. In addition, we will dissect the expression of titin isoforms at mRNA and protein level as well as address the molecular basis of the phenotypes. This includes the use of localization proteomics as an unbiased approach to characterize the protein environment of smooth muscle titin.The proposed work has implications for the care of patients with cardiomyopathies resulting from titin mutations contributing to a vascular phenotype.