Identifying genetic drivers of circulating metabolites associated with cardiac risk in pediatric chronic kidney disease
识别与儿童慢性肾病心脏风险相关的循环代谢物的遗传驱动因素
基本信息
- 批准号:10723371
- 负责人:
- 金额:$ 10.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcetyltransferaseAdultAgeAlanineBiochemicalBioinformaticsBiological MarkersBiometryBiostatistical MethodsCardiacCardiologyCardiovascular DiseasesCardiovascular systemCessation of lifeChildChild MortalityChildhoodChronic Kidney FailureClinicalClinical DataClinical ResearchComputational BiologyDataDevelopmentEchocardiographyEnrollmentEnzymesEpidemiologyEtiologyFacultyFeedbackFunctional disorderFundingFutureGenesGeneticGenetic VariationGenomicsGenotypeGlomerular Filtration RateGoalsGrantHeightHigh PrevalenceInterventionInvestigationK-Series Research Career ProgramsKnowledgeLearningLeftLeft Ventricular HypertrophyLeft Ventricular MassLinkManuscriptsMeasuresMediationMendelian randomizationMentorsMentorshipMetabolicMethodsNational Institute of Diabetes and Digestive and Kidney DiseasesNephrologyOutcomePathogenesisPediatric HospitalsPennsylvaniaPhiladelphiaPlasmaPopulationPreventionPrognostic MarkerProgram DevelopmentProspective cohortProspective, cohort studyProtocols documentationResearchResearch PersonnelResearch TrainingRiskRisk FactorsScienceShortening FractionSingle Nucleotide PolymorphismTrainingTranslatingTranslational ResearchUnited States National Institutes of HealthUniversitiesVentricular DysfunctionWorkagedcardiovascular injurycardiovascular risk factorcareercareer developmentcausal variantclinical practicedata resourcegenome wide association studygenomic dataindexinginstrumentmedical schoolsmetabolic phenotypemetabolomicsmolecular phenotypemortalitymultiple omicspressurepreventive interventionprogramssexskill acquisitionskillssymposiumtargeted treatmenttherapeutic developmenttherapeutic targettoolworking group
项目摘要
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.
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
在临床实践中对这一未充分检查人群的心脏危险因素进行治疗。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)继续接受指导和正式的教学
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。总的来说,
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Arthur Lee的其他文献
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