Mechanisms for nutritional programming of hypertension: identification of gatekeeper genes and proteins

怀孕期间母亲饮食的质量对发育中的胎儿的长期健康和福祉有很大的影响。胎儿期营养不良的人患冠心病和高血压的风险更大。值得注意的是，怀孕期间不同形式的营养不良，例如低蛋白质饮食或高脂肪饮食，会在后代中产生非常相似的疾病风险。这表明，在发育中的胎儿中，器官和组织的形式和功能的相对较小范围的变化可能是由营养应激源引发的。该项目的目的是确定驱动心血管疾病风险的早期生命规划的基本分子机制。这项工作将利用两种不同且成熟的程序性高血压动物模型，即大鼠的蛋白质限制和铁缺乏。这两种饮食限制都将在怀孕的关键阶段实施，并且在确定了饮食操纵的共同结果之后，我们将使用强大的现代分子技术来确定基因和蛋白质表达的变化，这些变化可能是调节早期营养与后期疾病风险之间关系的核心“看门人”。这项工作在发展胎儿营养和终身健康和疾病之间联系的机制基础的理解是重要的。这对公共卫生具有重大意义，因为越来越清楚的是，肥胖、糖尿病和心血管疾病的风险不仅仅是成年人生活方式因素的产物。生命任何阶段的风险都是从受孕开始的生命所有阶段中，包括营养不良在内的不利因素的累积暴露的产物。

The quality of the maternal diet during pregnancy is a powerful influence on the long-term health and well-being of the developing fetus. Individuals exposed to undernutrition in fetal life are at greater risk of coronary heart disease and hypertension. It is remarkable that very different forms of undernutrition in pregnancy, for example low protein diets or high fat diets, produce very similar profiles of disease risk in the resulting offspring. This suggests that a relatively narrow range of changes to the form and function of organs and tissues in the developing fetus, may be triggered by a nutritional stressor. The aim of this project is to identify the basic molecular mechanisms that drive the early life programming of cardiovascular disease risk. The work will utilise two distinct and well-established animal models of programmed hypertension, namely protein restriction and iron deficiency in the rat. Both dietary restrictions will be imposed during critical phases of pregnancy and, having established the common outcomes of the dietary manipulations, we will use powerful modern molecular techniques to identify changes in expression of genes and proteins that may be the central 'gatekeepers' that mediate the association between early life nutrition and later disease risk. This work is of importance in developing an understanding of the mechanistic basis of the link between fetal nutrition and lifelong health and disease. This is of major importance in terms of public health, as it is becoming clear that risk of obesity, diabetes and cardiovascular disease are not just a product of adult lifestyle factors. Risk at any stage of life is the product of cumulative exposures to adverse factors, including poor nutrition, at all stages of life from conception onwards.