Mechanisms of Sexual Dimorphism in Perinatal Programming

描述（由申请人提供）：许多人体研究表明， 出生时较小的婴儿成年后患心血管疾病的风险增加， 更大的婴儿，表明产前环境中的因素影响 胎儿的生长可以使个体日后心血管风险增加 生活中其中一个因素是母亲的蛋白质摄入量。在大鼠中，母体 蛋白质限制导致成人肾功能障碍和高血压 后代肾内肾素/血管紧张素系统在急性肾衰竭中的抑制作用 发育的关键时期，以及随之而来的肾单位减少 捐赠，似乎在这一方案中发挥了重要作用。女性 后代相对受到保护，不受几个 不利的母亲饮食条件，包括蛋白质限制。换句 动物模型，在发育过程中和/或在哺乳动物中性腺激素的存在， 成年有助于高血压的性二态模式，但 保护妇女不受为妇女制订方案的机制 母亲饮食引起高血压尚不清楚。 该项目的目的是确定负责执行《公约》的机制， 女性对围产期计划的相对保护作用 高血压最重要的假设是， 发育期间的睾酮和/或生命后期的睾酮或雌激素 负责围产期编程的两性异形， 特别是，这些性腺激素有助于编程， 后代高血压至少部分通过允许抑制 胎儿/新生儿肾内肾素血管紧张素系统和随后的损害， 肾脏发育，导致肾脏结构的永久性变化， 功能在这些研究中，男性和女性的睾丸激素和雌激素水平 正常和蛋白质限制的母亲的后代将在 发育期和/或成年期通过睾丸切除术/卵巢切除术， 给予外源性激素或通过给予药物 抑制剂的肾肾素-血管紧张素系统组分将在 新生儿期、动脉压、肾功能和肾小球数量 并测量幼年和成年动物的体积。

DESCRIPTION (provided by applicant): Numerous human studies have shown that babies born smaller have an increased adult cardiovascular risk compared to larger babies, indicating that factors in the prenatal environment affecting fetal growth can program the individual for increased cardiovascular risk later in life. One of these factors is maternal protein intake. In rats, maternal protein restriction leads to renal dysfunction and hypertension in the adult offspring. Suppression of the intrarenal rennin/angiotensin system during a critical period in development, and a consequent reduction in nephron endowment, appear to play an important role in this programming. Female offspring are relatively protected from the programming effects of several adverse maternal dietary conditions, including protein restriction. In other animal models, the presence of gonadal hormones during development and/or in adulthood contributes to the sexually dimorphic patterns of hypertension, but the mechanisms by which female gender protects against programming for hypertension by maternal diet are not known. The purpose of this project is to determine the mechanisms responsible for the relative protective effect of female Gender on perinatal programming for hypertension. The overarching hypothesis is that the presence or absence of testosterone during development and/or testosterone or estrogen later in life are responsible for the sexual dimorphism of perinatal programming, and specifically, that these gonadal hormones contribute to programming of offspring hypertension at least in part through permitting suppression of the fetal/newborn intrarenal renin angiotensin system and consequent impairment of renal development, resulting in permanent changes in renal structure and function. In these studies, testosterone and estrogen levels in male and female offspring of normal and protein-restricted mothers will be manipulated during the developmental period and/or in adult life by orchiectomy/ovariectomy and administration of exogenous hormone or by administration of pharmacologic inhibitors. Renal renin-angiotensin system components will be measured in the neonatal period, and arterial pressure, renal function, and glomerular number and volume will be measured in juvenile and adult animals.