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

基本信息

批准号：
10202680
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202680
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 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

项目摘要

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.

抽象的子宫收缩力由一个复杂的系统调节和控制，从而维持妊娠和分娩发生在妊娠 37 周之前，即足月时子宫协调收缩。早产 (PTL)，可能导致早产 (PTB)，影响 1500 万新生儿并导致 100 万人死亡鉴于宫缩是 PTL 的主要特征，因此使用宫缩抑制剂。在 PTB 管理中，目前的宫缩药物还不够有效，我们最近发现子宫平滑。来自小鼠和人类的肌肉（USM）细胞表达味觉苦味受体（TAS2R）及其经典信号成分（即 G 蛋白味觉素和 PLCβ2）。还有促苦味剂（例如菲咯啉 (PHEN)、和氯喹（一种 FDA 批准的抗疟药）可放松经宫缩剂预先收缩的子宫带（例如，催产素和前列腺素 F2α）比目前常用的宫缩抑制剂（即硝苯地平、此外，促苦味剂（例如氯喹）可以预防小鼠PTB。细菌内毒素脂多糖 (LPS) 和核孕酮受体拮抗剂 RU486 更常见在我们的初步研究中，我们进一步研究了比常用的宫缩抑制剂和味素依赖性方式。发现（1）PHEN可以阻止由血清素、内皮素-1诱导的怀孕小鼠子宫收缩，神经调节肽 S 和 U-46619，子宫中的所有病理生理介质，(2) USM 中的 Tas2r 表达为当怀孕小鼠接近临产时下降并在分娩后恢复，并且（3）同时因此，删除 USM 中表达的三个主要 Tas2rs 会增加小鼠发生 PTB 的可能性。提出 (1) TAS2R 是一类调节子宫收缩和妊娠持续时间的蛋白质，以及 (2) TAS2R 激动剂是广谱宫缩抑制剂，可能适合 PTB 管理。假设，我们将直接研究苦味剂如何激活TAS2R信号通路来放松人类然后我们将用药理学方法和 siRNA 慢病毒表达技术（目标 1）。使用 Tas2r 缺失小鼠来确定促苦味剂是否激活 TAS2R 导致 USM 松弛，以及 TAS2R 是否对于怀孕期间维持子宫静止、设定妊娠期至关重要最后，我们将研究促苦味剂在预防小鼠 PTB 方面的有效性。由 LPS 和 RU486 诱导，并确定 TAS2R 在促苦味剂预防 LPS- 或 RU486- 中的作用诱导 PTB（目标 3）。这项研究将揭示苦味剂使小鼠放松的分子机制。和人类子宫，确定 TAS2R 家族是否在怀孕期间子宫静止中发挥主要作用建立和分娩，TAS2R家族是否是治疗人类PTL的有吸引力的治疗靶点怀孕，并帮助确定是否可以将促苦味剂开发为新的、更有效的宫缩剂用于 PTB 管理。