Uterine bitter taste receptors in pregnancy and preterm labor management

子宫苦味受体在妊娠和早产管理中的作用

• 批准号: 10428573
• 负责人: Ronghua ZhuGe
• 金额: $ 34.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428573
• 关键词: 37 weeks gestation; Accounting; Affect; Agonist; Antimalarials; Asthma; Birth; CRISPR/Cas technology; Caring; Chloroquine; Chronic lung disease; Clinical; Complex; Contracts; Coupled; Development; Diabetes Mellitus; Disease; Effectiveness; Endothelin-1; Endotoxins; Etiology; FDA approved; Family; Fetus; Foundations; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic; Health; Hormones; Hour; Human; In Vitro; Indomethacin; Knockout Mice; Lead; Lipopolysaccharides; Magnesium Sulfate; Mediator of activation protein; Mifepristone; Molecular; Morbidity - disease rate; Mus; Muscle relaxation phase; Myometrial; Neurodevelopmental Disorder; Neuromedin U; Newborn Infant; Nifedipine; Nuclear; Obstetric pharmacology; Oxytocin; Pharmaceutical Preparations; Pharmacology; Phenanthrolines; Physiological; Play; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Premature Labor; Prevention; Probability; Progesterone Receptors; Prostaglandins; Proteins; Publishing; RNA Interference; Relaxation; Reproduction; Risk Factors; Role; Serotonin; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle; System; Taste Buds; Technology; Testing; Therapeutic; Tocolytic Agents; Tongue; Translational Research; United States; Uterine Contraction; Uterus; alpha-gustducin; analog; antagonist; base; cell type; developmental disease; disability; effective therapy; effectiveness evaluation; effectiveness study; expression vector; fetal; intergenerational; myometrium; neonatal death; novel; obstetrical complication; pediatric pharmacology; pregnant; prevent; rat Gnat3 protein; receptor; response; side effect; therapeutic target; uterine contractility; uterine smooth muscle cell; uterine smooth muscle contraction; 37 weeks gestation; Accounting; Affect; Agonist; Antimalarials; Asthma; Birth; CRISPR/Cas technology; Caring; Chloroquine; Chronic lung disease; Clinical; Complex; Contracts; Coupled; Development; Diabetes Mellitus; Disease; Effectiveness; Endothelin-1; Endotoxins; Etiology; FDA approved; Family; Fetus; Foundations; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic; Health; Hormones; Hour; Human; In Vitro; Indomethacin; Knockout Mice; Lead; Lipopolysaccharides; Magnesium Sulfate; Mediator of activation protein; Mifepristone; Molecular; Morbidity - disease rate; Mus; Muscle relaxation phase; Myometrial; Neurodevelopmental Disorder; Neuromedin U; Newborn Infant; Nifedipine; Nuclear; Obstetric pharmacology; Oxytocin; Pharmaceutical Preparations; Pharmacology; Phenanthrolines; Physiological; Play; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Premature Labor; Prevention; Probability; Progesterone Receptors; Prostaglandins; Proteins; Publishing; RNA Interference; Relaxation; Reproduction; Risk Factors; Role; Serotonin; Signal Pathway; Signal Transduction; Small Interfering RNA; Smooth Muscle; System; Taste Buds; Technology; Testing; Therapeutic; Tocolytic Agents; Tongue; Translational Research; United States; Uterine Contraction; Uterus; alpha-gustducin; analog; antagonist; base; cell type; developmental disease; disability; effective therapy; effectiveness evaluation; effectiveness study; expression vector; fetal; intergenerational; myometrium; neonatal death; novel; obstetrical complication; pediatric pharmacology; pregnant; prevent; rat Gnat3 protein; receptor; response; side effect; therapeutic target; uterine contractility; uterine smooth muscle cell; uterine smooth muscle contraction

Abstract Uterine contractility is regulated and controlled by a complex system such that pregnancy is maintained and parturition occurs at full term. Coordinated uterine contractions occurring prior to 37 weeks gestation, i.e., preterm labor (PTL), could lead to preterm birth (PTB) which affects 15 million newborns and causes 1 million neonatal deaths worldwide annually. Given that contractions are a central feature of PTL, tocolytics are used in PTB management, yet current tocolytics are not sufficiently effective. We recently found that uterine smooth muscle (USM) cells from mouse and human express bitter taste receptors (TAS2Rs) and their canonical signaling components (i.e., G-protein gustducin and PLCβ2). Also bitter tastants (e.g., phenanthroline (PHEN), and chloroquine, a FDA-approved antimalarial drug) relax uterine strips pre-contracted by uterotonics (e.g., oxytocin and prostaglandin F2α) more completely than current commonly used tocolytics (i.e., nifedipine, indomethacin and MgSO4). Moreover, bitter tastants (e.g., chloroquine) can prevent mouse PTB induced by bacterial endotoxin lipopolysaccharide (LPS) and nuclear progesterone receptor antagonist RU486 more often than commonly used tocolytics and in a gustducin dependent manner. In our preliminary studies, we further found that (1) PHEN can stop pregnant mouse uterine contractions induced by serotonin, endothelin-1, neuromedin S and U-46619, all pathophysiological mediators in the uterus, (2) Tas2r expression in USM is decreased when pregnant mice approach parturition and is restored after labor, and (3) the simultaneous deletion of the three main Tas2rs expressed in USM increases the probability of PTB in mice. We therefore propose that (1) TAS2Rs are a class of proteins regulating uterine contraction and gestational duration, and (2) TAS2R agonists are broad spectrum tocolytics potentially suitable for PTB management. To test these hypotheses, we will directly study how bitter tastants activate the TAS2R signaling pathway to relax human myometrium with pharmacological approaches and siRNA lentiviral expression technology (Aim 1). We will then use Tas2r deletion mice to determine whether bitter tastants activate TAS2Rs to cause USM relaxation, and whether the TAS2Rs are critical for maintaining uterine quiescence during pregnancy, setting gestational duration, in mice (Aim 2). Finally, we will study the effectiveness of bitter tastants in preventing mouse PTB induced by LPS and RU486, and determine the role of TAS2Rs in bitter tastants' prevention of LPS- or RU486- induced PTB (Aim 3). This study will uncover the molecular mechanisms by which bitter tastants relax mouse and human uteri, determine whether the TAS2R family plays a major role in uterine quiescence during pregnancy and parturition, establish whether the TAS2R family is an attractive therapeutic target for treating PTL in human pregnancy, and help determine whether bitter tastants can be developed as new and more effective tocolytics for PTB management.

抽象的 子宫收缩性受复杂系统的调节和控制，以维持怀孕，并 分娩全学期发生。在妊娠37周之前发生的协调子宫收缩，即 早产劳动（PTL）可能导致早产（PTB）影响1500万新生儿，并导致100万 每年在全球范围内新生儿死亡。鉴于收缩是PTL的主要特征 在PTB管理中，目前的溶解剂还不够有效。我们最近发现子宫光滑 来自小鼠和人类表达苦味受体（TAS2R）的肌肉（USM）细胞及其规范 信号传导成分（即G蛋白糖蛋白和PLCβ2）。还有苦味（例如，苯恐怖分子（phen）， 和氯喹，一种由FDA批准的抗疟药）松弛子宫条，由子宫毒作用（例如，例如， 催产素和前列腺素F2α）比当前常用的溶剂剂（即硝苯地平， 吲哚美辛和MGSO4）。此外，苦味（例如氯喹）可以防止小鼠PTB诱导 细菌内毒素脂多糖（LPS）和核孕激素受体拮抗剂RU486更常见 比常用的溶作剂和以古斯杜素依赖性的方式。在我们的初步研究中，我们进一步 发现（1）PEN可以阻止5-羟色胺Endophelin-1诱导的怀孕小鼠子宫收缩， NeuroMedin s和U-46619，子宫中的所有病理生理介质，（2）USM中的TAS2R表达是 当怀孕小鼠接近分娩并在分娩后恢复时，（3）简单 在USM中表达的三个主要TAS2R的删除增加了小鼠PTB的概率。因此，我们 建议（1）TAS2R是调节子宫收缩和妊娠持续时间的一类蛋白质，以及（2） TAS2R激动剂是可能适合PTB管理的广谱淋巴结剂。测试这些 假设，我们将直接研究苦味如何激活TAS2R信号传导途径以放松人 具有药物方法和siRNA慢病毒表达技术的肌层（AIM 1）。然后我们会 使用tas2r删除小鼠确定苦味是否激活tas2rs引起USM放松，并且 TAS2RS是否对于在怀孕期间保持子宫静止至关重要，设置妊娠 持续时间，在小鼠中（目标2）。最后，我们将研究苦味的苦味在防止小鼠ptb中的有效性 由LPS和RU486诱导，并确定Tas2rs在预防LPS或RU486-的苦味中的作用 诱导PTB（AIM 3）。这项研究将揭示苦味鼠标放松鼠标的分子机制 和人子宫，确定TAS2R家族在怀孕期间是否在子宫静止中起主要作用 和分娩，确定TAS2R家族是否是治疗人类PTL的有吸引力的治疗靶点 怀孕，并有助于确定是否可以发展为新的，更有效的滋味剂 用于PTB管理。