Identifying genetic drivers of circulating metabolites associated with cardiac risk in pediatric chronic kidney disease

项目摘要 心血管死亡是儿童慢性肾脏病（CKD）死亡的头号原因， 他们长大成人。目前对左室心肌梗死的生化病理生理学的认识有限， 心肌肥厚（LVH）和心室功能不全（VD）， 儿童CKD，缺乏针对性或预防性干预措施。代谢物与心脏 CKD儿童的结局已通过血浆非靶向代谢组学分析确定， 儿童慢性肾病（CKiD）研究。多组学研究可以更好地阐明 病理机制，并导致重大发现;然而，儿童CKD的研究有限。 该建议建立在以前的代谢组学工作的基础上，通过整合基因分型数据来确定致病基因， 代谢物轴与左LVH和VD的关系。这项工作旨在回答两个具体目标，1）如果有 是与循环代谢物水平相关的遗传变异，这些代谢物水平以前与 儿童CKD心血管结局和2）如果循环代谢物水平对LVH有因果影响， 儿童CKD中的VD。循环代谢物水平与单核苷酸多态性（SNP）的关联将 通过代谢组学-全基因组关联研究（mGWAS）分析进行评估。代谢物因果关系 将采用双向孟德尔随机化、利用基因型 数据作为工具变量。阐明儿童CKD中LVH和VD的病理生理学可能有助于 继续研究和开发治疗目标，帮助最终预防和 在临床实践中，在这一检查不足的人群中治疗心脏病风险因素。除了科学 追求这个职业发展奖，亚瑟李博士将作出重大进展，发展他的 作为一名独立的临床研究者。李博士的职业目标是1）扩展他的R38的科学性 代谢组学通过基因组学数据的整合工作，2）通过与 基因组学数据和多组学分析，以及3）继续接受导师和正式的教学 在基于大数据的临床研究方面的培训。李博士将定期会见他的主要导师和两个工作 小组，并将收到反馈意见，从他的指导委员会每季度。李博士将攻读硕士学位， 转化研究科学（MSTR），专注于生物信息学，推动未来 研究人员通过didactive课程，正式的导师计划，研究培训，专业技能 发展计划，以及对协议和赠款发展的指导。完成K38研究 将产生向国家会议提交的摘要和每个目标的第一作者手稿。总之， 该提案将作为通向NIH早期职业资助提案的桥梁，类似于R38 作为K38应用程序的管道。

PROJECT ABSTRACT Cardiovascular death is the number one cause of mortality for children with chronic kidney disease (CKD) once they reach adulthood. There is limited knowledge of the biochemical pathophysiology of left ventricular hypertrophy (LVH) and ventricular dysfunction (VD), prognostic markers of future adverse cardiac outcomes in pediatric CKD, and a dearth of targeted or preventive interventions. Metabolite associations with cardiac outcomes in children with CKD have been identified through plasma untargeted metabolomic profiling in the Chronic Kidney Disease in Children (CKiD) study. Multi-omics investigations can better elucidate pathomechanism and have to led to significant discoveries; however, studies in pediatric CKD have been limited. This proposal builds upon previous metabolomics work by integrating genotyping data to identify causal gene- metabolite axes with left LVH and VD in pediatric CKD. This work seeks to answer two specific aims, 1) if there is genetic variation associated with circulating metabolite levels that have been previously associated with pediatric CKD cardiovascular outcomes and 2) if circulating metabolite levels have causal effects on LVH and VD in pediatric CKD. Circulating metabolite levels' association with single nucleotide polymorphisms (SNPs) will be assessed through metabolomics-genome wide association studies (mGWAS) analyses. Metabolite causality on LVH and VD pathogenesis will be assessed with bidirectional Mendelian randomization, leverage genotype data as instrument variables. Elucidation of pathophysiology of LVH and VD in pediatric CKD may inform continued research investigations and development of therapeutic targets, aiding in the eventual prevention and treatment of cardiac risk factors in this underexamined population in clinical practice. In addition to the scientific pursuits of this career development award, Dr. Arthur Lee will make significant advances toward developing his career as an independent clinician investigator. Dr. Lee's career goals are to 1) extend the science of his R38 metabolomics work through the integration of genomics data, 2) gain skills in biostatistics by working with genomics data and multi-omics analyses, and 3) to continue receiving mentorship and formalized didactical training in large data-based clinical research. Dr. Lee will meet regularly with his primary mentor and two working groups, and will receive feedback from his mentoring committee quarterly. Dr. Lee will pursue a Masters of Science in Translational Research (MSTR), with a concentration in Bioinformatics, which advances future researchers through didactive coursework, a formal mentorship program, research training, professional skills development program, and guidance towards protocol and grant development. Completion of this K38 research will result in abstract submissions to national conferences and first-author manuscripts for each aim. Altogether, this proposal will serve as a bridge leading to a NIH early career funding proposal, analogous to how the R38 served as a pipeline to this K38 application.