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

项目摘要 有毒金属，包括镉（Cd）、汞（Hg）和铅（Pb），是已知的成人肾脏毒物; 然而，它们对发育中儿童的肾毒性研究不足。产前和幼儿期是潜在的 肾毒性金属的敏感窗口，因为这些生命阶段与发育有关， 肾过滤、分泌和重吸收系统的分化。本研究的目的是确定 生命早期暴露于重金属是否会导致儿童肾毒性，以及miRNAs是否 介导金属肾毒性。我在接触科学，表观遗传流行病学和 毒理学，并在K99期间获得了肾脏发育生理学和生物统计学方面的额外培训 获得独立之路奖。拟议的研究将解决创新的假设 关于儿童中毒性肾编程的起源。我将通过利用一个 在墨西哥城建立了纵向出生队列-肥胖规划研究， 环境和社会压力（PROGRESS）研究，该研究测量了肾毒性金属（镉，汞， 铅）纵向血液，头发，指甲以及血压，并收集尿液在每次访问。在 除了儿童血压外，拟议的研究还将检查肾脏疾病的临床前指标， 肾的三个离散区域中的功能障碍：肾小球、近端小管和远端肾单位（即， 远端小管和集合管）。将实现以下目标：1）确定是否产前/早期 生活金属暴露可预测儿童血压或肾功能生物标志物。2)套用一本小说 生物统计学方法能够“检测”金属相关的肾毒性，这是全球性的或位点特异性的， 离散的肾脏区域。3)检查尿miRNA作为金属-肾脏健康的生物标志物/介质的作用 关系。将测量的肾功能和健康生物标志物包括尿/血清肌酐， 电解质、渗透压以及血尿素氮和肾损伤的尿蛋白标志物。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。R 00研究 活动将导致科学报告和出版物，并将准备我成功竞争， R 01融资

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.