Developmental programming: influence of sex steroids and mechanisms

发育规划：性类固醇的影响和机制

• 批准号: 8383460
• 负责人: CHANDRASEKHAR YALLAMPALLI
• 金额: $ 36.41万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383460
• 关键词: Address; Adult; Affect; Angiotensins; Antiandrogen Therapy; Blood Pressure; Blood Vessels; Cardiovascular Physiology; Cell physiology; Chymosin; Data; Development; Disease; Endocrine; Endothelial Cells; Environment; Environmental Risk Factor; Epidemiology; Estradiol; Exposure to; Female; Fetal Development; Flutamide; Functional disorder; Gender; Goals; Gonadal Steroid Hormones; Growth; Health; Hormones; Human; Hypertension; Mesenteric Arteries; Modeling; Muscle function; Obesity; Orchiectomy; Organism; Ovariectomy; Perinatal Exposure; Plasma; Population; Predisposition; Prevention strategy; Proteins; Regulation; Regulatory Pathway; Renin-Angiotensin System; Reporting; Risk; Role; Severities; Sexual Development; Smooth Muscle; Smooth Muscle Myocytes; Steroid Receptors; Steroids; System; Testosterone; Variant; Vascular Endothelium; Vascular Smooth Muscle; age related; critical period; fetal programming; hypertension treatment; in utero; insight; male; offspring; pressure; prevent; programs; sex; steroid hormone; steroid hormone receptor

PROJECT SUMMARY Adverse intrauterine environment during the critical period of fetal development predisposes organisms to increased risk for developing hypertension. We and others using a low-protein (LP) model of fetal programming demonstrated that hypertension in offspring is gender related, with a greater effect in males than females, and endocrine changes may underlie the development of hypertension. The central hypothesis is that sex steroid hormones, testosterone (T) and estradiol (E2), via interaction with a variety of regulatory path- ways, regulate the development and progression of maternal LP-induced hypertension in the offspring. Effects include changes in vascular steroid receptors, endothelial and smooth muscle (VSM) function, and vascular rennin angiotensin system (RAS). Three specific aims are proposed. Specific Aim 1: Investigate the influence of sex steroids on maternal LP-induced developmental origins of hypertension in male and female offspring. Specific Aim 1a. Is the onset and severity of hypertension related to changes in sex steroids? We hypothesize that endocrine dysfunction will precede the development of hypertension with a more pronounced effect in males than females. Specific Aim 1b. Are alterations in blood pressure (BP) in the offspring specific to changes in the levels of sex steroids? We hypothesize that OVX in females exacerbates, while OCX in males dampens, the onset and severity of hypertension, and these changes are reversed by respective steroid replacement and flutamide. Growth rate, adiposity, and changes in MAP and plasma T and E2 will be assessed. Specific Aim 2: Characterization of endothelial and VSM cell functions and their regulation by sex steroids in hypertensive offspring. We hypothesize that endocrine dysfunction will alter expression of steroid receptors, endothelial, and VSM functions in LP offspring, and these effects are hormone specific. Specific Aim 2a. Are alterations in BP in the offspring specific to changes in the levels of sex steroid receptors? Specific Aim 2b. Is endothelial cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2c. Is VSM cell function altered and related to changes in T and E2 levels in hypertensive offspring? Specific Aim 2d. Are alterations in the function of endothelium and VSM specific to changes in T and E2 levels in hypertensive offspring? Specific Aim 3: Characterization of vascular RAS function and regulation by sex steroids in hypertensive offspring. We hypothesize that alteration in T and E2 levels will alter expression and activity of RAS components, and thus BP, in LP offspring. Specific Aim 3a. Is the function and expression of RAS components altered with age and related to changes in T and E2 levels in the hypertensive offspring? Specific Aim 3b. Are the expression and activity of RAS components in hyper- tensive offspring specific to changes in T and E2 using gonadectomy in LP offspring? The study will assess if these changes are reversed with respective hormones and flutamide. Collectively, these studies will yield important insights that could aid in developing sex-specific strategies for preventing and treating hypertension.

项目摘要 在胎儿发育的关键时期，宫内不良环境使生物易于生物 增加患高血压的风险。我们和其他人使用胎儿编程的低蛋白（LP）模型 证明后代的高血压与性别相关，对男性的影响比女性更大，并且 内分泌变化可能是高血压发展的基础。中心假设是性 类固醇激素，睾丸激素（T）和雌二醇（E2），通过与多种调节路径的相互作用 如何调节母体LP诱导的后代高血压的发展和进展。 影响包括血管类固醇受体的变化，内皮和平滑肌（VSM）功能， 和血管肾上腺血管紧张素系统（RAS）。提出了三个具体目标。具体目标1： 研究性类固醇对雄性LP诱导的高血压发育起源的影响 和女性后代。特定目标1a。是与性别变化有关的高血压的发作和严重程度 类固醇？我们假设内分泌功能障碍将在高血压发展之前 男性的影响比女性更明显。特定目标1B。是血压改变（BP） 性类固醇水平变化的后代？我们假设女性的OVX加剧了， 雄性OCX抑制了高血压的发作和严重程度，这些变化却被 各自的类固醇替代和氟氨酰胺。增长率，肥胖以及地图和等离子T的变化和 E2将进行评估。特定目标2：内皮和VSM细胞功能及其表征 性类固醇在高血压后代中调节。我们假设内分泌功能障碍会改变 LP后代中类固醇受体，内皮和VSM功能的表达，这些作用是激素 具体的。特定目标2a。是性类固醇水平变化的后代中BP的改变 受体？特定目标2B。内皮细胞功能是否改变并且与T和E2水平的变化有关 高血压后代？特定目标2C。 VSM细胞函数是否已改变，并且与T和E2水平的变化有关 在高血压后代？特定目标2D。是在特定于内皮的功能和VSM功能的改变 高血压后代T和E2水平的变化？特定目标3：血管RAS的表征 性类固醇在高血压后代的功能和调节。我们假设T和E2的改变 LP后代中的RAS组分，因此BP的表达和活性将改变水平。特定目标3A。是 RAS组件的功能和表达随着年龄的增长而改变，并且与T和E2水平的变化有关 高血压后代？特定目标3B。是RAS成分在高 - 的表达和活性 在LP后代使用GonadAdyCtomy的T和E2变化特有的腹侧后代？该研究将评估是否 这些变化用各自的激素和氟氨酰胺逆转。总的来说，这些研究将产生 重要的见解，可以帮助制定针对性的性别策略来预防和治疗高血压。