Mechanisms of Sexual Dimorphism in Perinatal Programming

描述(申请人提供)：大量的人体研究表明 与出生较小的婴儿相比，出生较小的婴儿成年后患心血管疾病的风险增加 较大的婴儿，表明产前环境中的因素影响 胎儿发育可以为个体日后心血管风险的增加做好准备 在生活中。其中一个因素是母亲的蛋白质摄入量。在大鼠身上，母体 限制蛋白质摄入会导致成人肾功能障碍和高血压 后代。肾内肾素/血管紧张素系统的抑制 在发育的关键时期，肾单位随之减少 捐赠，似乎在这一规划中发挥了重要作用。女性 后代相对受到保护，不受以下几种编程影响 不利的母亲饮食条件，包括蛋白质限制。在其他 动物模型，性腺激素在发育过程中和/或在 成年期有助于高血压的性二态模式，但 女性保护节目不被编排的机制 由母体饮食引起的高血压尚不清楚。 本项目的目的是确定负责 女性在围产期规划中的相对保护作用 高血压。最重要的假设是存在或不存在 发育期间的睾丸素和/或生命后期的睾丸素或雌激素 对围产期程序设计的性别二态负有责任，以及 具体地说，这些性腺激素有助于编程 子代高血压至少部分是通过允许抑制 胎儿/新生儿肾内肾素血管紧张素系统及其继发性损害 肾脏发育，导致肾脏结构和肾脏的永久性变化 功能。在这些研究中，男性和女性的睾丸激素和雌激素水平 正常母亲和蛋白质限制母亲的后代将在 切除/卵巢切除的发育期和/或成年生活 外源性激素给药或药物给药 抑制剂。肾脏肾素-血管紧张素系统成分将在 新生儿期、动脉压、肾功能和肾小球数量 而体积将在幼年和成年动物身上进行测量。

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.