FUNCTIONAL CORRELATIONS--SIGNALS TO SMOOTH MUSCLE MYOSIN

该项目的长期目标是确定新认可的、 调节血管、呼吸道和血管收缩的特定机制 其他平滑肌不受细胞内钙离子变化的影响。这个 主要的具体目标是：1.确定机制，体内动力学 以及上游监管机构和下游效应器，RAS通过这些机构 家族，单体GTP结合蛋白RhoA使平滑肌增敏 通过抑制去磷酸化的蛋白磷酸酶来抑制钙离子 调节肌球蛋白轻链，AN2，以确定 与钙离子变化无关的机制，加速 调节轻链的去磷酸化，从而松弛顺畅 肌肉。具体目标包括鉴定Rho相关蛋白。 在平滑肌中，Rho抑制平滑肌的机制 肌球蛋白轻链磷酸酶，以及测定其对 端粒蛋白的磷酸化及其在环状GMP-1中的新作用 激酶介导的钙离子脱敏作用。这项工作的另一个主要目标 该项目是在与结构生物学家的合作研究中， Rho及其相关蛋白对其结构的作用 端粒蛋白的磷酸化对其功能和晶体的影响 结构。该项目的广泛而普遍的意义来自于 RhoA可能参与了所有细胞类型和 平滑肌肌球蛋白调节亚基的存在及其功能 磷酸酶在非肌肉细胞中也存在；与健康相关的主要方面 这项研究源于平滑肌在调节中的重要性 血管和呼吸道的口径。很可能有一些形式 高血压和哮喘都是由于调节的异常 在这个项目中探索的路径，从 结晶学家非常密切的跨学科合作， 分子生物学家和两位细胞生理学家。

The long-term objective of this project is to determine newly recognized, specific mechanisms that regulate contraction of vascular, airway and other smooth muscle independently of changes in cellular calcium. The major specific aims are: 1., to determine the mechanism, in vivo kinetics and upstream regulators and downstream effectors through which the Ras family, monomeric GTP-binding protein RhoA sensitizes smooth muscle to calcium by inhibiting the protein phosphatase that de-phosphorylates the regulatory light chain of smooth muscle myosin, an 2., to determine the mechanisms that independently of changes in Ca2+, accelerate dephosphorylation of the regulatory light chain and, thereby, relax smooth muscle. The specific aims include identification of Rho-related proteins in smooth muscle, the mechanisms through which rho inhibits smooth muscle myosin light chain phosphatase, as well as determining the effects of phosphorylation of telokin and its novel putative role in cyclic GMP- kinase-mediated Ca2+-desensitization. An additional major goal of this project is to relate, in collaborative studies with structural biologists, the function of Rho and Rho-related proteins to their structures as well as the effect of phosphorylation of telokin on its function and crystal structure. The broad, general significance of the project derives from the involvement of RhoA in signalling in, probably, all cell types and the presence and function of the regulatory subunit of smooth muscle myosin phosphatase also in non-muscle cells; the major health related aspects of the research originate from the importance of smooth muscle in regulating the caliber of blood vessels and airways. It is probable that some forms of both hypertension and asthma are due to abnormalities of the regulatory pathways explored in this project that derives special strength from the very close interdisciplinary collaboration of a crystallographer, a molecular biologists and two cell physiologists.