Children's Exposure to Metals, MicroRNAs and Biomarkers of Renal Health

项目总结 镉(Cd)、汞(Hg)和铅(Pb)等有毒金属是已知的成年人肾脏毒物； 然而，它们对发育中儿童的肾脏毒性还没有得到充分的研究。产前和儿童早期是有潜力的 肾脏有毒金属的易感窗口，因为这些生命阶段与发育和 肾滤过、分泌和重吸收系统的区别。这项研究的目的是确定 生命早期接触重金属是否会导致儿童的肾脏毒性，以及miRNAs是否 中介金属肾毒性。我在接触科学、表观遗传学和流行病学方面有很强的基础 毒理学和肾脏发育生理学和生物统计学方面的额外培训 独立之路奖的阶段。拟议的研究将解决创新假说。 关于儿童有毒肾脏编程的起源。我将通过利用一个 在墨西哥城建立纵向出生队列--肥胖、生长规划研究 环境和社会压力(进展)研究，该研究测量了肾脏有毒金属(Cd、Hg、 对血液、头发、指甲和血压进行纵向监测，并在每次就诊时收集尿液。在……里面 除了儿童血压，这项拟议的研究还将检查肾脏的临床前指标 肾脏三个独立区域的功能障碍：肾小球、近端小管和远端肾单位(即肾小球、近端小管和远端肾单位)。 远端小管和集合管)。将实现以下目标：1)确定产前/早期 生命金属暴露可预测儿童血压或肾功能生物标志物。2)应用一部小说 生物统计学方法，使“检测”金属相关的肾毒性是全球性的或特定部位的 离散的肾脏区域。3)检查尿中miRNAs作为金属-肾脏健康的生物标志物/媒介的作用 两性关系。将测量的肾功能和健康生物标记物包括尿/血肌酐， 电解质，渗透压，以及血尿素氮和尿蛋白标记物的肾脏损伤。这些 这些发现将推动儿童肾脏健康领域的发展，并产生关于金属和 可能导致不良肾脏结局的病理生理学的特定机制。R00研究 这些活动将产生科学报告和出版物，并将为我成功竞争做好准备 R01基金。

PROJECT SUMMARY Toxic metals including cadmium (Cd), mercury (Hg), and lead (Pb) are known renal toxicants in adults; however, their renal toxicity in developing children is understudied. Prenatal and early childhood are potential susceptibility windows for renal toxic metals as these life stages are associated with development and differentiation of renal filtration, secretion, and reabsorptive systems. The aim of this study is to determine whether exposure to heavy metals early in life contributes to renal toxicity in children and whether miRNAs mediate metal nephrotoxicity. I have a strong foundation in exposure science, epigenetic epidemiology and toxicology and gained additional training in renal developmental physiology and biostatistics during the K99 phase of the Pathway to Independence award. The proposed research will address innovative hypotheses regarding the origins of toxic renal programming in children. I will conduct this research by leveraging an established longitudinal birth cohort in Mexico City - the Programming Research in Obesity, GRowth Environment and Social Stress (PROGRESS) study, which has measured levels of renal toxic metals (Cd, Hg, Pb) longitudinally in blood, hair, and nails as well as blood pressure, and collected urine at each visit. In addition to childhood blood pressure, the proposed research will examine preclinical indicators of renal dysfunction in three discrete regions of the kidney: the glomerulus, proximal tubule and distal nephron (i.e. distal tubule and collecting duct). The following aims will be accomplished: 1) Determine whether prenatal/early life metal exposure predicts childhood blood pressure or kidney function biomarkers. 2) Apply a novel biostatistical approach to enable “detection” of metal-associated renal toxicity that is global or site-specific in discrete kidney regions. 3) Examine the role of urinary miRNAs as biomarkers/mediators of metal-renal health relationships. Kidney function and health biomarkers that will be measured include urine/serum creatinine, electrolytes, osmolality, as well as blood urea nitrogen, and urine protein markers of kidney injury. These findings will advance the field of children's renal health as well as generate new hypotheses about metals and specific mechanisms that may contribute to the pathophysiology of adverse renal outcomes. The R00 research activities will results in scientific presentations and publications and will prepare me to successful compete for R01 funding.