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
项目成果
期刊论文数量(0)
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