FUNCTIONAL CORRELATIONS--SIGNALS TO SMOOTH MUSCLE MYOSIN

该项目的长期目标是确定新承认的， 调节血管、气道和呼吸道收缩的特定机制， 其他平滑肌细胞钙的变化无关。的 主要的具体目标是：1.，为了确定机制，体内动力学 以及上游调节子和下游效应子， 家族，单体GTP结合蛋白RhoA使平滑肌对 钙通过抑制蛋白磷酸酶去磷酸化 平滑肌肌球蛋白的调节轻链，2.，确定 独立于Ca 2+变化的机制， 调节轻链的去磷酸化，从而松弛平滑 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，以及确定 telokin的磷酸化及其在环GMP中的新的假定作用， 激酶介导的钙脱敏。另一个主要目标是 项目是与结构生物学家合作研究， Rho蛋白及其相关蛋白的结构功能 由于telokin的磷酸化对其功能和晶体的影响， 结构该项目的广泛、普遍意义来自于 RhoA可能参与所有细胞类型的信号传导， 平滑肌肌球蛋白调节亚单位的存在和功能 磷酸酶也在非肌肉细胞;主要的健康相关方面， 这项研究起源于平滑肌在调节 血管和气道的口径。很可能，某些形式 高血压和哮喘的发病都是由于 在这个项目中探索的途径，从 一位晶体学家，一位 分子生物学家和两名细胞生理学家。

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.