From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
基本信息
- 批准号:10241961
- 负责人:
- 金额:$ 16.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-20 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAdvisory CommitteesAffectAnimal ModelArterial Fatty StreakAtherosclerosisBase PairingBindingBiological AssayBiological ProcessBiologyCardiovascular DiseasesCause of DeathCell modelCell physiologyCellsChIP-seqChromatin Remodeling FactorChromosome 2ClonalityClustered Regularly Interspaced Short Palindromic RepeatsCodeComputational BiologyCoronary ArteriosclerosisCoronary arteryDataDevelopmentEnhancersEpigenetic ProcessEpithelialExcisionFundingGene Expression ProfilingGenesGeneticGenetic EpistasisGenetic ResearchGenetic RiskGenetic TranscriptionGenetic studyGenomeGenomic SegmentGoalsHeart DiseasesHumanHuman GeneticsIn VitroIndividualK-Series Research Career ProgramsLeadLesionLinkLuciferasesMADH3 geneMalignant NeoplasmsMediatingMentorsMesenchymalModelingMolecularMovementMusMyocardial InfarctionPersonsPhenotypePhysiciansPlayPrincipal InvestigatorProteinsRegulatory ElementResearch PersonnelResolutionRiskRoleRuptureScientistSignal PathwaySingle Nucleotide PolymorphismSmad ProteinsSmooth Muscle MyocytesStimulusTestingTrainingTranscription RepressorTranscriptional RegulationTranslatingUniversitiesUntranslated RNAWorkatherosclerosis riskbasecareercausal variantchromosome conformation capturedesigndisorder riskepigenetic profilingepigenome editingepigenomicsgenetic risk factorgenome editinggenome wide association studygenome-widegenomic locusin vivoin vivo Modelinsightmultiple omicsnovelnovel therapeuticspreventprogramspromoterresearch studyresponserisk variantscreeningskillstooltranscription factortranscriptome sequencingtranscriptomicstumorigenesis
项目摘要
ABSTRACT
Coronary artery disease (CAD) remains the leading cause of death in the U.S. and worldwide. Identifying
genetic risk factors and uncovering the underlying biological processes will lead to the development of much
needed new avenues for therapies. Decades of genetics research, especially genome wide association studies
(GWAS), have led to the discovery of numerous genetic loci associated with an increased risk for CAD.
However, the majority of these loci lie in non-protein-coding regions. Efforts are needed to identify causal
genes associated with these loci and the underlying cellular processes and signaling pathways. Recent
advances in epigenomic and transcriptomic profiling at unprecedented depth and resolution, along with
targeted genome/epigenome editing provide new opportunities to identify specific genes and cellular
mechanisms in CAD.
This K08 career development award is designed to launch the principal investigator’s career as an
independent physician scientist that utilizes complementary computational and molecular approaches to
discover the mechanisms that underlies human genetic risk to cardiovascular disease and translates these
findings into treatment. The principal investigator ‘s Mentor (Thomas Quertermous) is a world leader in
mechanistic studies of genetic risk of atherosclerosis. The proposed training is further supplemented by an
advisory committee of leaders in computational biology, genetics, and single-cell multi-omic analysis, including
Michael Snyder, Erik Ingelsson, William Greenleef, and Siddhartha Jaiswal, along with formal didactic courses
at Stanford University and Cold Spring Harbor.
Funded by an F32, the principle investigator used a combination of in vitro and in vivo models of
atherosclerosis and linked the non-coding CAD risk loci at 2q22 to ZEB2, a transcriptional repressor with a
critical role in cell-state transitions. ZEB2 appears to be specifically up-regulated in phenotypically modulated
smooth muscle cells (SMC) in atherosclerotic lesions, and modulates their cell-fate decisions. The proposed
study will: (1) identify the causal regulatory element(s) responsible for the CAD-Risk-associated region at 2q22;
(2) reveal the molecular mechanisms by which ZEB2 affects phenotypic modulation of SMC; (3) determine the
cellular mechanism by which perturbation of smooth muscle cell Zeb2 expression modulates atherosclerotic
lesions in vivo. The result of this study will elucidate new regulatory mechanisms that modulate atherosclerosis
biology. Additionally, the principle investigator will gain the training needed to transition into an independent
physician scientist focusing on translating genetic findings of human cardiovascular disease into specific
mechanisms and novel therapies.
摘要
项目成果
期刊论文数量(0)
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{{ truncateString('Paul Po Sheng cheng', 18)}}的其他基金
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
- 批准号:
10666553 - 财政年份:2020
- 资助金额:
$ 16.65万 - 项目类别:
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
- 批准号:
10469431 - 财政年份:2020
- 资助金额:
$ 16.65万 - 项目类别:
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
- 批准号:
10900886 - 财政年份:2020
- 资助金额:
$ 16.65万 - 项目类别:
From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease
从基因座到功能:ZEB2 在人类冠状动脉疾病风险中的作用
- 批准号:
10038543 - 财政年份:2020
- 资助金额:
$ 16.65万 - 项目类别:
The molecular mechanisms of SMAD3-mediated coronary disease risk
SMAD3介导的冠心病风险的分子机制
- 批准号:
9609402 - 财政年份:2018
- 资助金额:
$ 16.65万 - 项目类别:
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