Exploring the physiological, morphological and molecular bases of renal developmental programming.

胎儿和新生儿发育不佳会增加我们成年后患上一系列疾病的风险。发育过程中的有害事件可影响成人健康的概念被称为“发育规划”。获得一个健康的生命开端是澳大利亚政府的一个优先研究目标。肾脏特别容易受到发育程序的影响。这部分是因为肾脏的功能单位（肾单位）在人类出生前就已经形成了。因此，如果胎儿发育不理想，婴儿出生时就有永久性肾元缺陷的风险，从而导致功能和疾病的后果。我们在雄性大鼠身上发现，与正常饮食的大鼠相比，母鼠低蛋白饮食的后代肾单位更少，血压更低。这些老鼠在成年后对高盐饮食表现出惊人的敏感性。我们将定义这种敏感性的生理和形态学基础，并在女性中重复这些研究，因为越来越多的证据表明，在发育程序中存在显著的性别差异。确定发育规划的分子机制是该领域研究人员面临的最大挑战。我们最近完成了迄今为止对发育中的小鼠肾脏中基因表达的最全面的分析，并首次表明小鼠可以控制肾脏的发育。我们将利用基因组学和生物信息学的新技术来研究肾脏编程的分子机制。这些机制数据将为未来研究这些分子通路在所有哺乳动物物种发育规划中的具体作用提供一个很好的假设引擎。

Suboptimal fetal and neonatal development increases our risk of developing a range of diseases in adulthood. The concept that deleterious events during development can influence adult health is termed 'developmental programming'. Obtaining A Healthy Start to Life is a priority research goal of the Australian Government. The kidneys are particularly susceptible to developmental programming. This is in part because the functional units (nephrons) of the kidneys are all formed before birth in humans. Thus, if fetal development is suboptimal, babies are at risk of being born with a permanent nephron deficit, with functional and disease consequences. We have shown in male rats that the offspring of a maternal low protein diet have fewer nephrons and lower blood pressure than rats fed a normal diet. These rats display a striking sensitivity in adulthood to the feeding of a high salt diet. We will define the physiological and morphological bases of this sensitivity, and repeat these studies in females, as increasing evidence shows significant sex differences in developmental programming. Defining the molecular mechanisms of developmental programming is the greatest challenge for researchers in the field. We have recently completed the most comprehensive analysis to date of gene expression in the developing mouse kidney, and have shown for the first time that the mouse programmes kidney development. We will use the new techniques of genomics and bioinformatics to study the molecular mechanisms of kidney programming. This mechanistic data will provide an excellent hypothesis engine for future studies on the specific roles of these molecular pathways in developmental programming in all mammalian species.