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Uterine Relaxing Factors: Molecular Aspects of Action

子宫松弛因子：作用的分子方面

基本信息

批准号：
7863300
负责人：
BARBARA M SANBORN
金额：
$ 0.72万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7863300
关键词：
A kinase anchoring protein Affect Animal Model Animals Binding Binding Proteins Biochemical Calcineurin Cell Culture Techniques Cell Line Cell membrane Cells Cesarean section Cholesterol Complex Contracture Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Equilibrium Estrogens Fundus G Protein-Coupled Receptor Genes Generations Genetic Transcription Hormones Human Immunoblotting Labor Onset Lead Mediating Membrane Membrane Microdomains Membrane Proteins Methodology Methods Microscopic Modeling Molecular Muscle Myometrial Papio Pathway interactions Pattern Phospholipase C Phosphorylation Pregnancy Premature Labor Prevention Primates Progesterone Protein Kinase Rattus Regulation Regulatory Pathway Relative (related person)Relaxation Research Personnel Role Scaffolding Protein Signal Pathway Signal Transduction Staging Stretching Testing Time Tissues Woman Work design genetic regulatory protein improved in vivo membrane activity myometrium patch clamp pregnant programs protein distribution relaxing factor response uterine smooth muscle contraction

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this work is to understand the molecular mechanisms by which hormones influence uterine smooth muscle contraction and relaxation. This proposal focuses on defining cellular and subcellular mechanisms involved in crosstalk between major contractant and relaxant signaling pathways in the myometrium, in particular the role of scaffolding proteins and compartmentalization of signaling units in these mechanisms. Aim 1 will determine the mechanism responsible for the decline in myometrial plasma membrane-associated PKA prior to delivery in the pregnant rat and the relationship of this decline to the regulation of uterine contractile activity by cAMP. We will use a combination of muscle strip, cell culture and whole animal models to study basic mechanism and relate biochemical changes to effects on uterine contractile activity. Aim 2 will determine if similar changes in myometrial plasma membrane PKA occur in primate pregnancy in relation to labor. We will examine changes in tissue from both fundus and lower uterine segment in pregnant baboons at different stages in the transition from contractures to contractions and in myometrial tissues from women obtained at the time of cesarean section before or after the onset of labor. Mechanisms of regulation will be explored in vivo and in a pregnant human myometrial cell line. Aim 3 will determine the importance of the association of PKA and PP2B with AKAP79/150 in the control of myometrial PLCbeta3 phosphorylation. We will determine the phosphorylation status of PLCbeta3 in response to PKA activation in cells and tissue under conditions where we know Galpha(q) coupling is affected and will explore mechanisms by which PKA can influence activity and membrane association of itself, PP2B subunits and AKAP79/150 in cell culture and pregnant rat myometrial strip models. Aim 4 will determine how the constituents of OTR and cAMP regulatory pathways and K(Ca) channels are distributed between plasma membrane microdomains and assess whether distribution is affected by contractant or relaxant signals to influence signaling crosstalk. For these studies we will immunoblot, confocal microscopic immunolocalization and patch clamp methodology. Understanding the mechanisms for the changes in the influence of the cAMP pathway and signaling crosstalk balance will enhance understanding of myometrial activity during pregnancy and labor and may lead to design of improved methods for management of uterine contractile activity and the prevention of premature labor.

描述（由申请人提供）：这项工作的长期目标是了解激素影响子宫平滑肌收缩和舒张的分子机制。这项建议的重点是定义细胞和亚细胞机制参与的主要收缩和舒张信号通路之间的串扰在子宫肌层，特别是支架蛋白和区室化的信号单位在这些机制中的作用。目的1将确定机制负责子宫肌层质膜相关PKA的下降之前，在怀孕大鼠和这种下降的关系，以调节子宫收缩活动的cAMP。我们将使用肌条、细胞培养和整体动物模型的组合来研究基本机制，并将生化变化与对子宫收缩活动的影响联系起来。目的2将确定是否类似的变化，子宫肌层质膜PKA发生在灵长类动物妊娠与劳动。我们将检查子宫底部和子宫下段组织的变化在妊娠狒狒在不同阶段的过渡从挛缩到收缩和子宫肌层组织的妇女在剖腹产前或分娩后的时间。将在体内和妊娠人子宫肌层细胞系中探索调节机制。目的3将确定PKA和PP 2B与AKAP 79/150在子宫肌层PLC β 3磷酸化控制中的关联的重要性。我们将在已知Galalpha（q）偶联受影响的条件下，确定细胞和组织中响应PKA活化的PLC β 3的磷酸化状态，并将探索PKA在细胞培养和妊娠大鼠子宫肌条模型中影响自身、PP 2B亚基和AKAP 79/150的活性和膜结合的机制。目的4将确定OTR和cAMP调节途径和K（Ca）通道的成分如何分布在质膜微区之间，并评估分布是否受到收缩或舒张信号的影响，从而影响信号串扰。在这些研究中，我们将免疫印迹，共聚焦显微镜免疫定位和膜片钳方法。了解cAMP通路和信号串扰平衡影响的变化机制将增强对妊娠和分娩期间子宫肌层活动的理解，并可能导致设计用于管理子宫收缩活动和预防早产的改进方法。

项目成果

期刊论文数量（33）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long chain polyunsaturated fatty acids alter oxytocin signaling and receptor density in cultured pregnant human myometrial smooth muscle cells.

长链多不饱和脂肪酸会改变培养的孕妇肌层平滑肌细胞中的催产素信号和受体密度。

DOI：
10.1371/journal.pone.0041708
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Kim PY;Zhong M;Kim YS;Sanborn BM;Allen KG
通讯作者：
Allen KG

Relaxin increases calcium efflux from rat myometrial cells in culture.

松弛素增加培养物中大鼠子宫肌细胞的钙流出。

DOI：
10.1210/endo-119-1-435
发表时间：
1986
期刊：
Endocrinology
影响因子：
4.8
作者：
Rao,MR;Sanborn,BM
通讯作者：
Sanborn,BM

Effect of porcine relaxin on cyclic nucleotide levels and spontaneous contractions of the rat uterus.

猪松弛素对环核苷酸水平和大鼠子宫自发收缩的影响。

DOI：
10.1007/978-1-4613-3368-5_25
发表时间：
1982
期刊：
Advances in experimental medicine and biology
影响因子：
0
作者：
Sanborn,BM;Kuo,HS;Weisbrodt,NW;Sherwood,OD
通讯作者：
Sherwood,OD

Amino acids in the COOH-terminal region of the oxytocin receptor third intracellular domain are important for receptor function.

催产素受体第三胞内结构域COOH末端区域的氨基酸对于受体功能很重要。

DOI：
10.1152/ajpendo.00531.2005
发表时间：
2007
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
0
作者：
Zhong,Miao;Parish,Bridgette;Murtazina,DilyaraA;Ku,Chun-Ying;Sanborn,BarbaraM
通讯作者：
Sanborn,BarbaraM

Pathways used by relaxin to regulate myometrial phospholipase C.

松弛素调节子宫肌层磷脂酶 C 的途径。