Project 1 ENDOCRINE CASCADES AND PARTURITION: REGULATION

项目 1 内分泌级联和分娩：调节

• 批准号: 6896280
• 负责人: William E Rainey
• 金额: $ 29.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896280
• 关键词: adrenal glands; adrenocorticotropic hormone; biological signal transduction; chromatin immunoprecipitation; corticotropin releasing factor; cortisol; dehydroepiandrosterone; disease /disorder prevention /control; genetic regulation; genetic transcription; hormone receptor; hormone regulation /control mechanism; human fetus tissue; hydroxysteroid dehydrogenases; microarray technology; molecular biology; polymerase chain reaction; premature labor; protein isoforms; receptor expression; steroid hormone biosynthesis; tissue /cell culture; transfection /expression vector

While the signaling processes that regulate parturition are almost certainly multifactorial, there is considerable teleological evidence that the fetal adrenal glands act to influence the timing of labor. Near term the human fetal adrenals commence cortisol production and increase production of dehydroepiandrosterone-sulfate (DHEA-S), which acts as substrate for placental estrogen production. Fetal derived cortisol increases placental corticotropin releasing hormone (CRH) that initiates an endocrine feed-forward cascade that does not end until labor and separation of the fetus from the placenta. Increasing evidence supports the idea that estrogens and placental CRH act on the myometrium to initiate the transition from a quiescent to responsive contractile state, while cortisol alters fetal membrane prostaglandin production. The proposed research will define the mechanisms through which CRH directly activates the fetal adrenal gland thus initiating this feedforward endocrine cascade that ends in labor. To achieve these goals three aims are proposed: Specific Aim 1 will define the CRH receptors and signaling pathways that regulate fetal adrenal production of cortisol and DHEA-S. The goal of this aim is to define the CRH receptor isoform that regulates the fetal adrenal, determine the intracellular signaling pathways used by CRH to regulate cortisol and DHEA-S biosynthesis, determine the mechanism regulating adrenal expression of CRH receptors and define the pattern of CRH receptor expression. The goal of Specific Aim 2 is to define the chronic effects of CRH on the capacity of fetal adrenal cells to produce cortisol and DHEA-S. During most of gestation the fetal adrenal gland expresses little 3beta-hydroxysteroid dehydrogenase (HSD3B2) making cortisol production impossible. Elevated levels of CRH in the second half of gestation coincide with the initiation of fetal adrenal cortisol biosynthesis and expression of HSD3B2. In Aim 2 we will determine CRH gene targets that promote fetal adrenal production of cortisol via activation of HSD3B2 gene transcription. Specific Aim 3 will determine if CRH increases fetal adrenal responsiveness to ACTH leading to the dramatic activation of steroid production seen in the last weeks of gestation. This effect of CRH would explain what was thought to be the conflicting observation that circulating levels of ACTH do not increase during the last trimester when fetal adrenal steroidogenesis most increases. Completion of the goals set forth in this application will determine how CRH activates the fetal adrenal glands late in gestation and will provide important details into endocrine controls of normal and preterm labor.

虽然调节分娩的信号传导过程几乎肯定是多因素的，但 大量目的论证据表明胎儿肾上腺会影响分娩时间。近期，人类胎儿肾上腺开始产生皮质醇，并增加硫酸脱氢表雄酮 (DHEA-S) 的产生，DHEA-S 是胎盘雌激素产生的底物。胎儿来源的皮质醇会增加胎盘促肾上腺皮质激素释放激素 (CRH)，从而启动内分泌前馈级联反应，直到分娩和胎儿与胎盘分离时才会结束。越来越多的证据支持这样的观点：雌激素和胎盘 CRH 作用于子宫肌层，启动从静止状态向反应性收缩状态的转变，而皮质醇则改变胎膜前列腺素的产生。拟议的研究将 定义了 CRH 直接激活胎儿肾上腺的机制，从而启动这种前馈内分泌级联反应，最终导致分娩。为了实现这些目标，提出了三个目标： 具体目标 1 将定义调节胎儿肾上腺皮质醇和 DHEA-S 产生的 CRH 受体和信号通路。该项目的目标是定义调节胎儿肾上腺的CRH受体亚型，确定CRH用于调节皮质醇和DHEA-S生物合成的细胞内信号通路，确定调节CRH受体的肾上腺表达的机制并定义CRH的模式受体表达。具体目标 2 的目标是确定 CRH 对胎儿肾上腺细胞产生皮质醇和 DHEA-S 的能力的慢性影响。在妊娠的大部分时间里，胎儿肾上腺几乎不表达 3β-羟基类固醇脱氢酶 (HSD3B2)，因此不可能产生皮质醇。妊娠后半期 CRH 水平升高与胎儿肾上腺皮质醇生物合成和 HSD3B2 表达的开始一致。在目标 2 中，我们将确定 CRH 基因靶点，通过激活 HSD3B2 基因转录来促进胎儿肾上腺皮质醇的产生。具体目标 3 将确定 CRH 是否会增加胎儿肾上腺对 ACTH 的反应，从而导致妊娠最后几周类固醇产生的急剧激活。 CRH 的这种作用可以解释被认为是相互矛盾的观察结果，即在妊娠最后三个月，当胎儿肾上腺类固醇生成最多时，ACTH 循环水平并未增加。完成本申请中提出的目标将确定 CRH 如何在妊娠后期激活胎儿肾上腺，并将提供 正常和早产的内分泌控制的重要细节。