Role of Progesterone in Colonic Muscle Dysfunction

描述（由申请方提供）：由于结肠惯性引起的慢性便秘在育龄女性中很常见，在西方国家的患病率为20%，女性：男性比例为9：1。然而，其在细胞水平上的发病机制尚不清楚。妊娠并发症是妊娠期常见的并发症，与血清孕酮（PC）水平升高有关。PG主要通过基因组作用影响胃肠平滑肌的运动。我们的初步研究表明，结肠惯性的女性患者的肌细胞中的信号转导异常类似于PG在体外人结肠肌细胞中诱导的信号转导异常，以及在体内和体外用PG处理的豚鼠的肌细胞中诱导的信号转导异常。因此，拟议的研究旨在扩大这些调查的机制，PG损害收缩，增加豚鼠和人类的正常结肠肌肉的松弛，并测试假设，女性结肠惯性是由于更大的肌肉反应PG由于PG受体的过度表达。该假说基于异常G蛋白模式，其影响信号转导，该信号转导有助于基础结肠运动[MI]的发生，介导G蛋白偶联受体（GPCR）依赖性激动剂的作用，并损害其与受体的结合以及PG受体mRNA水平的增加。因此，我们建议确定：a）由于异源三聚体和单体G蛋白的变化，PG的基因组作用改变了信号转导，B）这些G蛋白的变化具有显著的功能后果，损害基础和激动剂诱导的结肠运动，以及这种异常运动反应是否局限于G蛋白依赖性激动剂，c）前列腺素（PGF 2a）有助于基础MI的发生，其作用和合成被PC抑制。d）PG处理引起正常人结肠肌肉中的信号转导异常，其似乎与患有结肠惰性的女性中存在的信号转导异常相似。e）患有结肠惰性的女性中的肌肉异常可以通过PG受体的过表达来解释。这些研究将在对照、PG给药和妊娠豚鼠的肌细胞和肌条中进行，并在腺癌患者和结肠惯性和慢性便秘女性患者乙状结肠游离缘的正常和PG给药人结肠肌细胞中进行。

DESCRIPTION (provided by applicant): Chronic constipation due to colonic inertia is common in females of reproductive age with a 20% prevalence in Western countries and a female: male ratio of 9:1. Its pathogenesis at the cellular level, however, is unknown. Constipation is a frequent complication of pregnancy and correlates with rising serum levels of progesterone (PC). PG affects the motility of the gastrointestinal smooth muscle primarily through genomic actions. Our preliminary studies have shown signal transduction abnormalities in muscle cells from female patients with colonic inertia similar to those induced by PG in human colonic muscle cells in vitro and in muscle cells from guinea pigs treated with PG in vivo and in vitro. The proposed studies are therefore aimed at extending these investigations on the mechanisms whereby PG impairs contraction and increases relaxation in normal colonic muscle from guinea pigs and humans and to test the hypothesis that female colonic inertia is due to a greater muscle response to PG due to an over expression of PG receptors. This hypothesis is based on an abnormal G protein pattern that affects the signal transduction that contributes to the genesis of basal colonic motility [MI] and mediates the actions of G protein coupled receptor (GPCR) dependent agonists and impairs their binding to receptors as well as an increased mRNA levels of PG receptors. We therefore propose to determine that: a) PG's genomic actions alter the signal transduction due to changes in heterotrimeric and monomeric G proteins, b) These G protein changes have significant functional consequences impairing the basal and agonist induced colonic motility and whether this abnormal motor response is confined to agonists that are G protein dependent, c) Prostaglandin's (PGF2a) contribute to the genesis of basal MI and its actions and synthesis inhibited by PC. d) PG treatment causes signal transduction abnormalities in normal human colonic muscle that appear to be similar to those present in females with colonic inertia, e) The muscle abnormalities in females with colonic inertia could be explained by an over expression of PG receptors. These studies will be conducted in muscle cells and strips from control, PG treated and pregnant guinea pigs, and in normal and PG treated human colonic muscle cells from free margins of the sigmoid colon of patients with adenocarcinoma and from female patients with colonic inertia and chronic constipation.