PHOSPHOLAMBAN MODULATION OF SMOOTH MUSCLE CONTRACTILITY

受磷蛋白（Phospholamban，PLB）是一种抑制SR Ca ~（2+）-ATP酶的蛋白质。 PLB的磷酸化在体外缓解了这种抑制，并且存在 PLB在体内调节心肌收缩力的实质性证据。 有一些证据表明PLB在平滑肌中具有类似的作用。 最近，博士Evangelia Kranias已经产生了PLB“淘汰赛”（PLB-） 老鼠. 研究者建议使用该小鼠作为模型进行研究 PLB在体内平滑肌中的作用。 初步数据 提出来支持PLB是一种重要调节剂的假设 细胞间Ca 2+和平滑肌的重要决定因素 收缩性该项目有三个具体目标。 在第一个目标中， 研究者建议量化和比较平滑 与年龄匹配的野生型小鼠相比，PLB-小鼠的肌肉中的肌肉。 的 最初的研究将集中在紧张性主动脉和相位门静脉， 代表性血管制备物和纵向回肠， 气管制剂，代表肠道和气道光滑 肌肉. 这些研究也将扩展到阻力动脉。 的 PLB在基线收缩功能中的作用，以及其在 将测定由CAMP或CGMP途径介导的松弛。 在 为此，研究人员还将核实野生PLB的存在 类型的肌肉，并建立这种蛋白质和Ca 2 +- ATP酶 第二个目标将测试假设， PLB-平滑肌的收缩性是由于Ca 2+处理的变化 这是由于SR功能的改变。 这些测试将包括荧光 （Ca 2+）I的测量和SR Ca 2+的特异性抑制剂的使用 释放和Ca 2+吸收。 该目标的一个目标是确定 研究潜在机制的性质， 以弥补公共小巴的不足。 第三个目标是确定 PLB缺乏对体内Ca 2+泵速率的影响，以及 量化正常人中泵的PLB抑制的基线水平 组织.

Phospholamban (PLB) is a protein which inhibits the SR Ca2+-ATPase. Phosphorylation of PLB relives this inhibition in vitro and there is substantial evidence that PLB modulates cardiac contractility in vivo. There is some evidence for a similar role for PLB in smooth muscle. Recently, Dr. Evangelia Kranias has produced a PLB "knockout" (PLB-) mouse. The investigator proposes to use this mouse as a model to study the role of PLB in smooth muscle in vivo. Preliminary data are presented to support the hypothesis that PLB is an important modulator of intercellular Ca2+ and a significant determinant of smooth muscle contractility. This project has three specific aims. In the first aim, the investigator proposes to quantitate and compare contractility in smooth muscle from the PLB- mouse to that in age-matched wild type mice. The initial studies will focus on the tonic aorta and the phasic portal vein as representative vascular preparations and the longitudinal ileum and trachea preparations, representative of enteric and airway smooth muscle. These studies will also be extended to resistance arteries. The role of PLB in baseline contractile functions, as well as its importance in relaxation mediated by CAMP or CGMP pathways will be determined. In this Aim the investigator will also verify the presence of PLB in wild type muscles and establish the levels of this protein and of the Ca2+- ATPase. The second Aim will test the hypothesis that alterations in contractility in PLB-smooth muscles are due to changes in Ca2+ handling attributable to altered SR function. These tests will include fluorescent measurements of (Ca2+)I and the use of specific inhibitors of SR Ca2+ release and Ca2+ uptake. A goal of this aim is to determine the magnitude and investigate the nature of potential mechanisms that may compensate for the absence of PLB. The third aim is to determine the effects of the absence of PLB on the Ca2+ pump rate in vivo, and to quantify the baseline level of PLB inhibition of the pump in normal tissue.