Gender and perinatal origins of adult disease

成人疾病的性别和围产期起源

• 批准号: 6595223
• 负责人: LORI L WOODS
• 金额: $ 31.28万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6595223
• 关键词: blood pressure; cardiovascular disorder risk; developmental nutrition; dietary proteins; dietary restriction; estrogens; gender difference; histogenesis; histopathology; hormone regulation /control mechanism; hypertension; kidney; kidney function; laboratory rat; male castration; mother /embryo /fetus nutrition; nutrition related tag; ovariectomy; renal glomerulus; renin angiotensin system; testosterone

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 restrict leads to renal dysfunction and hypertension in the adult offspring. Suppression of the intrarenal renin 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 relative protected from the programming effects of several adverse maternal dietary conditions, including protein restriction. In other model, the presence of gonadal hormones during development and/or in adulthood contribute 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 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 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.

许多人类研究表明，出生时较小的婴儿与较大的婴儿相比，成年心血管风险增加，这表明产前环境中影响胎儿生长的因素可以使个体在以后的生活中增加心血管风险。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年后代的肾功能障碍和高血压。在发展的关键时期，肾内肾素血管紧张素系统的抑制，以及随之而来的肾单位捐赠的减少，似乎在这一编程中发挥了重要作用。雌性后代相对受到保护，免受几种不利的母体饮食条件（包括蛋白质限制）的编程影响。在其他模型中，发育期间和/或成年期性腺激素的存在有助于高血压的性二态模式，但女性性别通过母体饮食保护免于高血压编程的机制尚不清楚。本项目的目的是确定机制，负责相对保护作用的女性围产期规划高血压。总体假设是，发育过程中睾酮和/或发育过程中睾酮和/或生命后期睾酮或雌激素的存在或缺乏是围产期编程的性二态性的原因，具体来说，这些性腺激素至少部分地通过抑制胎儿/新生儿肾内的肾素来促进后代高血压的编程。血管紧张素系统和随之而来的肾脏发育受损，导致肾脏结构和功能的永久性变化。在这些研究中，将在发育期和/或成年期通过睾丸切除术/卵巢切除术和给予外源性激素或通过给予药理学抑制剂来控制正常和蛋白质限制性母体的雌性后代的睾酮和雌激素水平。将在新生期测量肾脏肾素-血管紧张素系统组分，并将在幼龄和成年动物中测量动脉压、肾功能以及肾小球数量和体积。