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）：胎儿发育关键期的不利宫内环境使生物体容易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，男性的影响比女性更大，内分泌的变化可能是高血压发生的基础。核心假设是，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 LP 诱发的后代高血压的发生和进展。影响包括血管类固醇受体、内皮和平滑肌 (VSM) 功能以及血管肾素血管紧张素系统 (RAS) 的变化。提出了三个具体目标。具体目标 1：研究性类固醇对母体 LP 诱导的雄性和雌性后代高血压发育起源的影响。具体目标 1a。高血压的发病和严重程度与性类固醇的变化有关吗？我们假设内分泌功能障碍将先于高血压的发生，并且对男性的影响比对女性更明显。 具体目标 1b。后代血压（BP）的变化是否与性类固醇水平的变化有关？我们假设女性中的 OVX 会加剧高血压的发作和严重程度，而男性中的 OCX 会减弱，并且这些变化可以通过相应的类固醇替代品和氟他胺来逆转。将评估生长率、肥胖以及 MAP 和血浆 T 和 E2 的变化。具体目标 2：高血压后代内皮细胞和 VSM 细胞功能的表征及其性类固醇的调节。我们假设内分泌功能障碍会改变 LP 后代的类固醇受体表达、内皮细胞和 VSM 功能，并且这些影响是激素特异性的。 具体目标 2a。后代血压的变化是否与性类固醇受体水平的变化有关？ 具体目标 2b。高血压后代的内皮细胞功能改变是否与 T 和 E2 水平的变化有关？ 具体目标 2c。 VSM 细胞功能改变是否与高血压后代 T 和 E2 水平的变化有关？具体目标 2d。内皮和 VSM 功能的改变是否与高血压后代 T 和 E2 水平的变化有关？具体目标 3：高血压后代血管 RAS 功能的表征和性类固醇的调节。我们假设 T 和 E2 水平的改变将改变 LP 后代中 RAS 成分的表达和活性，从而改变 BP。 具体目标 3a。 RAS 成分的功能和表达是否随年龄而改变，并与高血压后代中 T 和 E2 水平的变化有关吗？ 具体目标 3b。高血压后代中 RAS 成分的表达和活性是否与 LP 后代性腺切除后 T 和 E2 的变化有关？该研究将评估这些变化是否可以通过相应的激素和氟他胺逆转。总的来说，这些研究将产生重要的见解，有助于制定预防和治疗高血压的针对性别的策略。 公共卫生相关性：成人健康和疾病的规划似乎取决于胎儿接触各种子宫内环境因素。许多胎儿编程模型和人类流行病学数据表明，高血压易感性存在性别依赖性差异。该提案将产生重要的见解，有助于制定预防和治疗高血压的针对性别的策略。