REGULATION OF PULMONARY VASCULAR TONE

候选人的长期职业目标是了解这些机制 调节肺血管张力，以期这将 最终改善对肺动脉高压患者的治疗。他的 研究已经从对患者和清醒动物的研究发展到 对分离的血管和细胞的研究。这一变化是由 坚信目前的肺动脉高压治疗是无效的 由于对监管的基本机制了解不足 肺血管张力。这项提议的科学重点是 了解血管收缩剂和血管扩张剂介导的信号转导 肺血管组织。调查员的研究小组将转移到 犹他大学将利用与专家的合作机会 细胞生物学(约翰R.霍达尔博士)，细胞内钙离子(威廉·H。 和信号转导(斯蒂芬·M·普雷斯科特博士和盖伊·A。 齐默尔曼)。建议的实验结合了生物化学和生理学。 测量。第一个具体目标将定义肺脏的影响 血管收缩药对肺血管45Ca~(++)进入和释放的影响 肺动脉内皮细胞和平滑肌细胞内钙离子浓度。 第二个具体目标将检验这样一种假设，即血管收缩剂 激活磷脂酰肌醇循环，这些产物有助于 通过增加细胞内Ca~(+4)浓度和激活血管收缩 蛋白激酶C这一特定的目标将决定血管收缩剂 刺激1，2-二酰基甘油的生产和水解物 肺动脉内皮细胞和平滑肌细胞中的肌醇磷脂。 这些产品的重要性将通过研究 磷脂酶C和蛋白激酶C抑制剂对激动剂诱导的作用 肺血管收缩。第三个特定的ALM将确定 CAMP或cGMP预防激动剂诱导的能力 血管收缩。这一具体目标也将决定 CAMP和cGMP对激动剂诱导的细胞内钙内流的影响 4+的释放，1，2二酰甘油的形成或1，2二酰甘油的水解 磷脂酰肌醇。第四个具体的ALM将研究其机制 通过肺血管收缩抑制血管扩张剂的作用。 我们将研究这种功能性拮抗的可能机制。 包括一种假设，即蛋白激酶C的激活抑制了 异丙肾上腺素刺激百日咳引起的环磷酸腺苷升高 毒素敏感的鸟嘌呤核苷酸调节蛋白(GI或GO)。这个 拟议的研究将通过以下方式更好地理解这些机制 哪种血管收缩药和血管扩张剂单独或协同作用来控制 肺血管张力。

The candidate's long-term career objective is to understand the mechanisms that regulate pulmonary vascular tone in the expectation that this will eventually improve therapy for patients with pulmonary hypertension. His research has evolved from studies in patients and awake animals to the study of isolated vessels and cells. This change has been driven by the conviction that Current therapy for pulmonary hypertension is ineffective because of inadequate understanding of the basic mechanisms that regulate Pulmonary vascular tone. The scientific focus of this proposal is to understand vasoconstrictor and vasodilator mediated signal transduction in pulmonary vascular tissue. The investigator's research group is moving to the University of Utah to take advantage of colla ration with experts in cell biology (Dr. John R. Hoidal), intracellular Ca++ (Dr. William H. Barry), and signal transduction (Dr. Stephen M. Prescott and Dr. Guy A. Zimmerman). The proposed experiments combine biochemical and physiological measurements. The first specific aim will define the effects of pulmonary vasoconstrictors on 45 Ca++ entry in pulmonary vessels and the release of intracellular Ca++ in pulmonary artery endothelial and smooth muscle cells. The second specific aim will test the hypothesis that vasoconstrictors activate the phosphatidylinositol cycle and that these products contribute to vasoconstriction by increasing intracellular Ca +4 and activating protein kinase C. This specific aim will determine whether vasoconstrictors stimulate the production of 1,2 diacylglycerols and hydrolysis of phosphoinositides in pulmonary artery endothelial and smooth muscle cells. The importance of these products will be tested by studying the effect of inhibitors of phospholipase C and protein kinase C on agonist-induced pulmonary vasoconstriction. The third specific alm will determine the ability of cyclic AMP or cyclic GMP to prevent agonist-induced vasoconstriction. This specific aim will also determine the effects of cyclic AMP and cyclic GMP on agonist-induced Ca++ entry, intracellular Ca 4+ release, and the formation of 1,2 diacylglycerols or the hydrolysis of phosphoinositides. The fourth specific alm will investigate the mechanisms by which pulmonary vasoconstrictors inhibit the action of vasodilators. Possible mechanisms for this functional antagonism will be studied including the hypothesis that activation of protein kinase C inhibits the increase in cyclic AMP caused by isoproterenol by stimulating a pertussis toxin sensitive guanine nucleotide regulatory protein (Gi or Go). The proposed research will lead to a better understanding of the mechanisms by which vasoconstrictors and vasodilators act alone and in concert to control pulmonary vascular tone.