Smooth Muscle Thin Filament

描述(申请人提供)：周围的肌肉光滑。 中空器官的外围，收缩以改变器官形状或保持张力 固定形状，从而控制生命体液的流动，这些体液是 对心血管、呼吸系统的正常运作至关重要， 消化系统和生殖系统。如果对平滑肌的调节 收缩功能不正常，它可能会导致以下疾病 高血压、哮喘和早产。我们工作的目标是 了解正常收缩调节的分子基础。平滑 肌肉收缩主要受钙离子调控 粗丝中肌球蛋白的磷酸化。然而，没有严格的 磷酸化水平和由此产生的 收缩力。有证据表明，在 肌动蛋白细丝可能涉及原肌球蛋白(TM)。然而， 其作用机制目前尚不清楚。这样做的长期目标是 该项目旨在揭示TM与 其他细丝蛋白，调节平滑肌收缩。主 这一建议的假设是，细丝调节主要发生在 粗大肌球蛋白控制TM在细丝上的运动 细丝和其他细丝蛋白，钙蛋白和钙蛋白，它们 又受磷酸化和钙结合蛋白的调节。这将是 通过监测TM的位置来测试，通过测量TM-肌动蛋白来测试 距离与肌球蛋白、钙调素和钙调素的关系 共振能量转移及其与肌动球蛋白ATPase活性的相关性 体外模拟收缩。这些研究的结果，将是 对重组的粗细长丝进行的研究，将有助于进一步 对平滑肌收缩的通断和通断的认识 平滑肌肉的独特能力，特别是血管肌肉，保持 张力，因此器官的形状，以非常少的能量为代价。这些研究 将比较来自血管和胃肠道平滑肌肉的肌球蛋白 以更好地了解血管肌肉维持这种张力的能力。

DESCRIPTION (provided by the applicant): Smooth muscles, which surround the periphery of hollow organs, contract to change organ shape or maintain tension to fix the shape and thereby control the flow of vital fluids, which are essential to the normal functioning of the cardiovascular, respiratory, digestive, and reproductive systems. If the regulation of smooth muscle contraction does not function properly, it could contribute to such diseases as high blood pressure, asthma, and premature birth. The goal of our work is to understand the molecular basis of the normal regulation of contraction. Smooth muscle contraction is primarily regulated by the Ca2+ controlled phosphorylation of myosin in the thick filament. However there is not a strict coupling between phosphorylation levels and the level of the resulting contractile force. Evidence indicates that there is additional regulation in the actin thin filament possibly involving tropomyosin (Tm). However the mechanism of this function is poorly understood. The long-range goal of this project is to uncover the molecular mechanisms whereby Tm, in concert with other thin filament proteins, regulates smooth muscle contraction. The main hypothesis of this proposal is that thin filament regulation occurs mainly by controlling the movement of Tm on the thin filament by myosin in the thick filament and by the other thin filament proteins, caldesmon and calponin, which are in turn regulated by phosphorylation and Ca2+binding proteins. This will be tested by monitoring Tm's position, and movement by measuring the Tm-actin distances as a function of myosin, caldesmon and calponin by fluorescence resonance energy transfer and correlated with actomyosin ATPase activity, an in vitro analogue of contraction. The results of these studies, which will be conducted on reconstituted thick and thin filaments, will help to further our understanding of the switching on/off of smooth muscle contraction and of smooth muscle's unique ability, especially vascular muscle, to maintain tension, and thus organ shape, at the cost of very little energy. These studies will compare myosin from vascular and gastrointestinal smooth muscles in order to better understand the ability of vascular muscle to maintain this tension.