Gender Bias in Gastrointestinal Motility in Health and Diabetes

胃肠(GI)运动是性二态的。在女性中，胃肠道动力会随着荷尔蒙的变化而变化 在月经周期和怀孕期间。然而，在认识和理解上存在差距。 雌激素的作用及其调节胃肠动力和胃肠动力周期依赖性改变的机制 运动障碍。与经典核受体ERα、ERβ不同，膜结合G蛋白偶联激活 雌激素引起的雌激素受体(GPER)启动快速的细胞事件。我们已经获得了初步证据 研究表明，GPER在平滑肌中表达，并与AC/cAMP/PKA通路偶联，介导肌肉 放松胃部和结肠部。GPER KO小鼠的平滑肌表现为松弛丧失 GPER激动剂的反应为GPER在平滑肌松弛中的作用提供了证据。GI中转是 与低雌激素间情期相比，高雌激素发情前期和发情期雌性小鼠的发情延迟， 和雄鼠。胃肠道转运中这些性别和周期相关的变化与 GPER的表达和功能。在这些初步数据的基础上，提出了检验假设的研究 胃肠道转运的性别和周期依赖性变化是由于GPER的表达和功能的变化 再加上AC/cAMP/PKA通路的激活和平滑肌松弛(特异性目标1)。 胃肠动力障碍也是性二态的。与糖尿病相关的发病率更高 与男性相比，女性的胃瘫和便秘。血管平滑肌功能受损的作用 而GPER在胃肠动力障碍的性别二型性中的作用尚未得到充分的研究。 糖尿病。初步研究表明，糖尿病患者血管内皮细胞GPER的表达减少 这种减少是通过氧化应激引起的表观遗传调节的改变而介导的 H3在赖氨酸残基4上的三甲基化(H3K4me3)和H3在赖氨酸残基27上的乙酰化(H3K27ac) GPER基因启动子区域。Rna-seq数据结合热图分析显示， 选择性组蛋白脱乙酰酶在糖尿病小鼠血管中的表达增加了…… GPER KO小鼠的平滑肌中也存在氧化应激，提示氧化应激增加 糖尿病应激可能是由于GPER表达减少所致。在初步数据的基础上，研究了 提出检验糖尿病氧化应激增加下调GPER表达的假说 通过GPER启动子H3K4me3和H3K27ac的减少以及GPER介导的保护作用的丧失 氧化应激导致cAMP/cGMP信号转导、肌肉松弛和胃肠道转运减少(特定目标2)。 从我们的研究中获得的知识旨在提供对所涉及的细胞机制的见解 胃肠动力的性别和周期依赖性变化。女性性别特异性的未知潜在病因 糖尿病相关胃肠动力障碍的突出突出强调了拟议研究的临床意义。

Gastrointestinal (GI) motility is sexually dimorphic. In women, GI motility varies with hormonal changes during the menstrual cycle and pregnancy. However, there is a gap in the knowledge and understanding the role of estrogen and the mechanism by which it regulates sex- and cycle-dependent changes in GI motility and dysmotility. Unlike classical nuclear receptors ERα, ERβ, activation of membrane-bound G protein-coupled estrogen receptor (GPER) by estrogen initiates rapid cellular events. We have obtained preliminary evidence to show that GPER is expressed in smooth muscle and is coupled to AC/cAMP/PKA pathway to mediate muscle relaxation in the stomach and the colon. Smooth muscle from GPER KO mice exhibited loss of relaxation in response to GPER agonist providing evidence for a role of GPER in smooth muscle relaxation. GI transit was delayed in female mice of high-estrogen proestrus and estrus phases compared to low-estrogen diestrus phase, and male mice. These sex- and cycle-dependent changes in GI transit are associated with changes in the expression and function of GPER. Based on these preliminary data, studies are proposed to test the hypothesis that sex- and cycle-dependent changes in GI transit are due to changes in expression and function of GPER coupled to activation of AC/cAMP/PKA pathway and smooth muscle relaxation (Specific Aim 1). GI motility disorders are also sexually dimorphic. There is greater prevalence of diabetes-associated gastroparesis and constipation in women compared to men. The contribution of impaired smooth muscle function and role of GPER in smooth muscle has not been fully explored in sexual dimorphism in GI dysmotility in diabetes. Preliminary studies showed that expression of GPER was decreased in smooth muscle from diabetic mice and the decrease is mediated via oxidative stress-induced changes in epigenetic regulation via a decrease in trimethylation of H3 at lysine residue 4 (H3K4me3) and acetylation of H3 at lysine residue 27 (H3K27ac) at the promoter region of GPER gene. RNA-seq data combined with heatmap analysis showed an increase in the expression of selective histone deacetylase (HDACs) in smooth muscle from diabetic mice. An increase in oxidative stress was also obtained in smooth muscle from GPER KO mice suggesting the increase in oxidative stress in diabetes could be due to a decrease in GPER expression. Based on the preliminary data, studies ae proposed to test the hypothesis that an increase in oxidative stress in diabetes downregulates GPER expression via decrease in H3K4me3 and H3K27ac of GPER promoter, and loss of GPER-mediated protection against oxidative stress leads to decrease in cAMP/cGMP signaling, muscle relaxation and GI transit (Specific Aim 2). Knowledge gained from our study is intended to provide insights into the cellular mechanisms involved in sex-and cycle-dependent changes in GI motility. The unknown underlying etiology of female sex-specific prominence of diabetes-associated GI dysmotility underscores the clinical significance of the proposed studies.