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：
7781360
负责人：
IAIN L BUXTON
金额：
$ 24.84万
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/7781360
关键词：
Address Agonist Alternative Splicing Binding Biochemical Biological Calcium Caveolae Cavia Cell membrane Cells Cholesterol Cyclodextrins Decidua Detergents Development Enzymes Equilibrium Failure Family Global Change Glycolipids Goals Guanosine Guanylate Cyclase Hormonal Human Interphase Cell Isoenzymes Lead Leucine Zippers Lipids Measures Membrane Methods Molecular Molecular Target Muscle Muscle Cells Myometrial Myosin ATPase Nature Nitric Oxide Particulate Pathway interactions Peptides Phosphoric Monoester Hydrolases Phosphorylation Physiological Pregnancy Pregnant Uterus Premature Labor 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 new therapeutic target paracrine pregnant premature 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自早产中人类肌层所独有或改变的信号转导机制，因为这目前是未知的，并且因为当前对早产（PTL）的治疗完全不足。无论在任何给定妇女中，PTL（胎儿或母体）的不同原因，在无法解释的情况下，都会在肌层信号传导途径或其激活/失活的时机中不可避免地发生变化。我们将采用人和豚鼠肌层细胞和组织的实验方法，这些方法将融合，以了解早产的平滑肌机制，并提供一个或多个以前不知道的治疗靶标。因为肌层静止与一氧化氮诱导的CGMP全球升高无关；虽然颗粒状鸟叶基环酶的肽激活剂（PGC型C）以CGMP依赖性的方式松弛肌层，但我们建议在当前对肌层平滑肌中CGMP作用的理解中存在一个难题。我们将研究以下假设：PGC激活后的CGMP升高存在并作用于与可溶性鸟叶基环酶不同的隔室。我们提出，肌层PGC被划分为肌细胞小窝和/或富含脂质的膜筏，以及PKG的已知能力增加钙的吸收能力，可通过PKG通过PKG进行pkg II来激活肌动蛋白磷酸酶（MP）的同素Zipper Zipper（MP）的激活，该蛋白质酶（MP）的激活Zipper（Mp）的激活量PKGII。反过来，这降低了RMLC的磷酸化，从而促进了子宫肌肉的松弛。可溶性鸟叶叶尼环酶激活剂对子宫肌的松弛虽然导致CGMP的积累，但在一个可溶的室中确实与富含脂质的富含脂质的信号传导结构域保持平衡，并且尽管激活了PKGI，但并不会导致MP的激活。我们提出，通过PKGI作用的细胞可溶室中的CGMP不会调节肌层平滑肌的松弛。使用生理，生化和分子方法探索我们在子宫平滑肌中的假设将进一步了解我们对肌层静止的调节。发现肌层信号的精确和独特性质将使人们更好地了解劳动和早产劳动的调节，并可能导致PTL中的新治疗靶标。