REGULATION OF MYOMETRIAL RELAXATION: AGONIST-SPECIFIC cGMP ACTION

子宫肌层松弛的调节：激动剂特异性 cGMP 作用

基本信息

批准号：
7201882
负责人：
IAIN L BUXTON
金额：
$ 27.7万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-05 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7201882
关键词：
Address Agonist Alternative Splicing Binding Biochemical Biological Calcium Caveolae Cavia Cell membrane Cells Cholesterol Cyclodextrins Decidua Detergents Development Disruption Elevation Enzymes Equilibrium Failure Family Global Change Glycolipids Goals Guanosine Guanylate Cyclase Hormonal Human Interphase Cell Isoenzymes Lead Leucine Zippers Lipids Localized Measures Membrane Methods Molecular Molecular Target Muscle Muscle Cells Myometrial Myosin ATPase Nature Nitric Oxide Particulate Pathway interactions Patient currently pregnant Peptides Phosphoric Monoester Hydrolases Phosphorylation Physiological Pregnancy Pregnant Uterus Premature Labor Prematurity of fetus Process Protein Binding Protein Isoforms Proteins Regulation Relaxation Research Research Proposals Sarcoplasmic Reticulum Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Soluble Guanylate Cyclase Therapeutic Time Tissues Tocolytic Agents Uterine Contraction Uterine Gland Woman cGMP-dependent protein kinase Ibeta design fetal guanylin indium arsenide myometrium myosin phosphatase novel therapeutics paracrine prevent receptor research study response therapeutic target tool uptake uroguanylin

项目摘要

DESCRIPTION (provided by applicant): Our research objective is to determine the signal transduction mechanisms that are unique to, or altered in the human myometrium in preterm labor because this is presently unknown and because current treatments for premature labor (PTL) are wholly inadequate. No matter the varied causes of PTL (fetal or maternal) in any given woman, in unexplained cases, changes will inevitably be found in myometrial signaling pathways or the timing of their activation/inactivation. We will take experimental approaches in human and guinea pig myometrial cells and tissues that will converge in an understanding of the smooth muscle mechanisms of prematurity and provide one or more therapeutic targets not previously known. Because myometrial quiescence is independent of nitric oxide induced global elevations of cGMP; while the peptide activator of particulate guanylyl cyclase (pGC-Type C) relaxes the myometrium in a cGMP-dependent fashion, we suggest that a conundrum exists in our current understanding of cGMP action in myometrial smooth muscle. We will investigate the hypothesis that the cGMP elevation following activation of pGC exists and acts in a compartment distinct from that of soluble guanylyl cyclase. We propose that myometrial pGC is compartmented to myocyte caveolae and/or lipid-rich membrane rafts and, together with the known ability of PKG to increase the uptake of calcium into sarcoplasmic reticulum, acts via PKG Type II to activate a myosin phosphatase (MP) isozyme containing a leucine zipper that permits its activation by PKGII. This in turn lowers the phosphorylation of the rMLC and thus promotes relaxation of uterine muscle. Relaxation of the myometrium by activators of soluble guanylyl cyclase, while leading to the accumulation of cGMP, does so in a soluble compartment that is not in equilibrium with the lipid-rich signaling domain and does not lead to activation of MP despite activation of PKGI. We propose that cGMP in the soluble compartment of the cell acting via PKGI does not regulate relaxation of myometrial smooth muscle. Exploring our hypotheses in uterine smooth muscle with physiological, biochemical and molecular methods will further our understanding of the regulation of myometrial quiescence. Discovery of the precise and unique nature of myometrial signaling will lead to a better understanding of the regulation of labor and preterm labor and may lead to new therapeutic targets in PTL.

描述（由申请人提供）：我们的研究目标是确定早产中人类子宫肌层特有或改变的信号转导机制，因为目前尚不清楚，而且目前对早产（PTL）的治疗完全不够。无论任何女性 PTL（胎儿或母体）的原因多种多样，在无法解释的情况下，子宫肌层信号通路或其激活/失活时间都不可避免地会发生变化。我们将在人类和豚鼠的子宫肌层细胞和组织中采取实验方法，这些方法将集中于对早产儿平滑肌机制的理解，并提供一种或多种以前未知的治疗靶点。因为子宫肌层静止与一氧化氮诱导的 cGMP 整体升高无关；虽然颗粒鸟苷酸环化酶（pGC-C 型）的肽激活剂以 cGMP 依赖性方式松弛子宫肌层，但我们认为，我们目前对子宫肌层平滑肌中 cGMP 作用的理解存在一个难题。我们将研究以下假设：pGC 激活后 cGMP 升高存在，并在与可溶性鸟苷酸环化酶不同的区室中发挥作用。我们认为，子宫肌层 pGC 被划分为肌细胞小凹和/或富含脂质的膜筏，并且与已知的 PKG 增加肌浆网钙摄取的能力一起，通过 PKG II 型发挥作用，激活肌球蛋白磷酸酶 (MP)含有亮氨酸拉链的同工酶，可被 PKGII 激活。这反过来又降低了 rMLC 的磷酸化，从而促进子宫肌肉松弛。可溶性鸟苷酸环化酶激活剂使子宫肌层松弛，同时导致 cGMP 积累，但这是在可溶性区室中进行的，该区室与富含脂质的信号结构域不平衡，并且尽管 PKGI 激活，但不会导致 MP 激活。我们认为，细胞可溶性区室中的 cGMP 通过 PKGI 起作用，并不调节子宫肌层平滑肌的松弛。用生理、生化和分子方法探索子宫平滑肌的假设将进一步加深我们对子宫肌层静止调节的理解。发现子宫肌层信号传导的精确和独特性质将有助于更好地了解分娩和早产的调节，并可能导致 PTL 的新治疗靶点。