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: 8056426
• 负责人: CHANDRASEKHAR YALLAMPALLI
• 金额: $ 38.25万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056426
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Programming of adult health and disease appears to be dependent upon fetal exposure to various in utero environmental factors. Many models of fetal programming and epidemiological data in humans suggest gender-dependent variation in the susceptibility to hypertension. This proposal will yield important insights that could aid in the development of sex-specific strategies for the prevention and treatment of hypertension.

描述(由申请人提供)：在胎儿发育的关键时期，不利的宫内环境使生物体容易患高血压的风险增加。我们和其他人使用低蛋白(LP)胎儿编程模型表明，后代高血压与性别有关，男性比女性影响更大，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，睾酮(T)和雌二醇(E2)，通过与多种调节途径相互作用，调节母体脂蛋白诱导的子代高血压的发生和发展。影响包括血管类固醇受体、血管内皮细胞和平滑肌(VSM)功能以及血管肾素血管紧张素系统(RAS)。提出了三个具体目标。具体目的1：研究性类固醇对母血清脂蛋白诱导的男性和女性子代高血压的发生发展的影响。具体目标1a。高血压的发病和严重程度是否与性激素的变化有关？我们假设内分泌功能障碍将先于高血压的发展，对男性的影响比女性更明显。具体目标1b。子代血压(BP)的变化是否与性激素水平的变化有关？我们假设，女性的OVX会加剧高血压的发病，而男性的OCX会抑制高血压的发病和严重程度，而这些变化分别被类固醇替代和氟他胺逆转。将评估生长速度、肥胖度以及MAP和血浆T和E2的变化。具体目标2：高血压子代血管内皮细胞和血管内皮细胞功能的特征及其受性类固醇的调节。我们假设内分泌功能障碍会改变LP后代的类固醇受体、内皮细胞和VSM功能的表达，并且这些影响是激素特异性的。具体目标2a。子代血压的变化是否与性激素受体水平的变化有关？具体目标2b。高血压子代的内皮细胞功能是否改变并与T和E_2水平的变化有关？具体目标2c。高血压子代的VSM细胞功能是否改变并与T和E2水平的变化有关？具体目标2d。高血压子代T和E_2水平的改变是否与血管内皮功能和VSM功能的改变有关？具体目标3：高血压子代血管RAS功能的特征和性激素的调节。我们假设T和E_2水平的改变将改变LP后代中RAS组分的表达和活性，从而改变BP。具体目标3a。RAS组分的功能和表达是否随着年龄的变化而改变，并与高血压后代T和E2水平的变化有关？具体目标3b。高血压子代中RAS组分的表达和活性是否与LP子代摘除性腺时T和E2的变化有关？这项研究将评估这些变化是否会被各自的激素和氟他胺逆转。总而言之，这些研究将产生重要的见解，有助于制定针对性别的预防和治疗高血压的策略。 公共卫生相关性：成人健康和疾病的规划似乎取决于胎儿暴露于各种宫内环境因素。人类的许多胎儿编程模型和流行病学数据表明，高血压的易感性随性别而异。这项建议将产生重要的见解，有助于制定针对性别的高血压预防和治疗战略。