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可以肯定是多因素的 胎儿肾上腺作用会影响劳动时间的大量目的论证据。近期人类胎儿肾上腺开始生产皮质醇，并增加脱氢表硫酮硫酸盐（DHEA-S）的产生，这是胎盘雌激素产生的底物。胎儿衍生的皮质醇会增加胎盘皮质激素释放激素（CRH），该激素（CRH）启动了内分泌喂养前级别的级联反应，该级联反应直到分娩和胎儿与胎盘分离。越来越多的证据支持了以下观点：雌激素和胎盘CRH对子宫骨架作用以启动从静止的收缩状态过渡，而皮质醇会改变胎儿膜前列腺素的产量。拟议的研究将 定义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，结束于劳动。为了实现这些目标，提出了三个目标：特定目标1将定义调节皮质醇和DHEA-S胎儿肾上腺产生的CRH受体和信号传导途径。该目的的目的是定义调节胎儿肾上腺的CRH受体同工型，确定CRH用于调节皮质醇和DHEA-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-S-Signal途径，确定调节CRH受体肾上腺表达的机制并定义CRH受体表达的模式。特定目标2的目的是定义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。在大多数妊娠期间，胎儿肾上腺几乎没有3beta-羟基固醇脱氢酶（HSD3B2），使皮质醇产生不可能。妊娠后半段的CRH水平升高与胎儿肾上腺皮质醇生物合成和HSD3B2的表达相吻合。在AIM 2中，我们将确定通过激活HSD3B2基因转录来促进皮质醇的胎儿肾上腺产生的CRH基因靶标。具体目标3将确定CRH是否会增加胎儿肾上腺对ACTH的反应性，从而导致妊娠最后几周的类固醇产生的急剧激活。 CRH的这种作用将解释是矛盾的观察结果，即在胎儿肾上腺类固醇发生大部分时，循环水平不会增加。完成本应用程序中设定的目标的完成将决定CRH在妊娠后期如何激活胎儿肾上腺，并将提供 对正常和早产的内分泌控制的重要细节。