Integrated cellular, mouse and human research on a novel missense variant influencing adiposity in Samoans
Integrated cellular, mouse and human research on a novel missense variant influencing adiposity in Samoans
批准号:
9175412
负责人:
Stephen T. McGarvey
金额:
$78.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-09-01 至 2020-04-30
关键词:
AdipocytesAdipose tissueBehavioralBiologicalBiologyBody WeightBody mass indexCREB3 geneCell SurvivalCell modelCellsCultured CellsDataDietDiseaseDrosophila genusEnergy MetabolismEnvironmentEnvironmental Risk FactorEpidemiologyEthnic groupFatty acid glycerol estersFundingFutureGenesGeneticGenetic EpistasisGenotypeGoalsHealthHeart DiseasesHeritabilityHigh PrevalenceHomeostasisHomologous GeneHumanIndividualInterventionKnock-inKnock-in MouseLeadLipidsMammalsMeasuresMediatingMedical GeneticsMetabolicMetabolismMinorityMissionMolecularMorbidity - disease rateMultivariate AnalysisMusNutritionalObesityObesity associated diseaseOrganismOutcomeParticipantPathogenesisPathway interactionsPhenotypePhysical activityPhysiologicalPopulationPreventionPreventiveProcessPublic HealthQuantitative Trait LociResearchResourcesRoleSamoaSamoanStarvationStressTechniquesTestingTherapeuticTherapeutic InterventionTissuesTranscriptional RegulationUnited States National Institutes of HealthVariantWorkbaseclinically relevantflygenetic approachgenetic variantgenome wide association studyhuman subjectimprovedinnovationknock-downlipid biosynthesismortalitymultidisciplinarynovelnutritionobesity riskobesity treatmentoverexpressionoxidationpleiotropismpreventresponserisk varianttraittranscription factor
中文摘要
项目摘要
在这次竞争性更新中,我们专注于表征一种新的错义变体,该变体是通过基因组鉴定的,
广泛关联分析(GWAS)的肥胖相关性状在萨摩亚人在前一个资助期间。这
错义变异与体重指数(BMI)高度相关,其效应量大于任何其他变量
已知的常见肥胖风险变体。含有这种错义变体的基因编码一种假定的转录
一种最近被认为与果蝇的能量代谢有关,但仍然很弱的TF因子
特别是在高等生物中。本申请中提供的初步数据表明,
野生型人基因及其错义变体在3 T3 L1脂肪细胞中的过表达增强了
脂肪生成,促进脂质储存,并改善细胞存活。此外,错义基因的过度表达
变体促进更大的脂质储存并减少能量底物氧化,这表明它是一种
“节俭”变体。考虑到肥胖对疾病的巨大贡献,迫切需要进行更多的研究
以了解这种错义变异导致人类肥胖的机制。中央
这个建议的目的是确定TF基因和它的错义变体如何贡献能量
体内平衡,并确定介导这些影响的转录途径。我们将实现这一目标
利用细胞、小鼠和人类的综合研究,了解分子、生理和临床
错义变体的相关性。将追求以下具体目标:目标1将确定和
表征介导TF基因及其错义变体对能量的影响的基因网络
在培养的细胞中的稳态和能量底物代谢,一系列代谢相关的组织,
小鼠和123名萨摩亚人的脂肪组织; Aim 2将描述错义变体对
使用变异体特异性
敲入小鼠;目标3将更精确地表征错义变体对代谢和
影响500名萨摩亚GWAS参与者的能量稳态的行为特征,
根据他们的基因型进行选择。这些更深层次的表型将在萨摩亚进行新的实地考察,
重新联系最初GWAS研究的参与者,在此期间,
将测试与目标1和2中使用的条件/暴露类似的条件/暴露;目标4将更全面地表征
使用包括测试选择性签名的综合统计方法的错义变体,
通过多变量分析检测多效性,进行通路分析,检测错义变体x
环境相互作用,重点是饮食和体力活动,测试TF基因x基因相互作用
重点关注目标1和2中鉴定的基因,并检测与来自
目标3:这些目标的成功完成将促进对肥胖及其下游的认识
健康结果以及确定药物干预的新靶点。
英文摘要
PROJECT SUMMARY
In this competitive renewal we focus on characterizing a novel missense variant that was identified by genome-
wide association analysis (GWAS) of obesity-related traits in Samoans during the previous funding period. This
missense variant is highly associated with body mass index (BMI) with an effect size greater than any other
known common obesity risk variant. The gene harboring this missense variant encodes a putative transcription
factor (TF) that has recently been implicated in energy metabolism in Drosophila but remains poorly
characterized, particularly in higher organisms. Preliminary data presented in this application indicate that
overexpression of both the wild-type human gene and its missense variant in 3T3L1 adipocytes enhances
adipogenesis, promotes lipid storage, and improves cell survival. In addition, overexpression of the missense
variant promotes even greater lipid storage and reduces energy substrate oxidation, suggesting that it is a
“thrifty” variant. Given the enormous contribution of obesity to disease, additional studies are urgently needed
to understand the mechanisms by which this missense variant contributes to obesity in humans. The Central
Aim of this proposal is to determine how the TF gene and its missense variant contribute to energy
homeostasis and to identify the transcriptional pathways mediating these effects. We will achieve this goal
using integrated studies in cells, mice, and humans to understand the molecular, physiological, and clinical
relevance of the missense variant. The following Specific Aims will be pursued: Aim 1 will identify and
characterize the gene networks mediating the effects of the TF gene and its missense variant on energy
homeostasis and energy substrate metabolism in cultured cells, a range of metabolically-relevant tissues from
mice, and adipose tissue from 123 Samoans; Aim 2 will characterize the impact of the missense variant on
whole body and tissue-specific energy homeostasis and energy substrate metabolism using variant-specific
knockin mice; Aim 3 will more precisely characterize the impact of the missense variant on metabolic and
behavioral traits that impact energy homeostasis in a subset of 500 Samoans GWAS participants who will be
selected based on their genotype. These deeper phenotypes will be measured with new fieldwork in Samoa by
re-contacting participants from the original GWAS study, during which metabolic and nutritional
conditions/exposures analogous to those used in Aims 1 and 2 will be tested; Aim 4 will more fully characterize
the missense variant using comprehensive statistical approaches including testing for selective signatures,
testing for pleiotropy via multivariate analyses, performing pathway analyses, testing for missense variant x
environment interactions with a focus on diet and physical activity, testing for TF gene x gene interactions
focusing on genes identified in Aims 1 and 2, and testing for association with newly gathered phenotypes from
Aim 3. Successful completion of these aims will promote the understanding of obesity and its downstream
health outcomes as well as identify novel targets for pharmacological interventions.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Diabetes Care in American Samoa
-
批准号:8072928
-
项目类别:
-
资助金额:$9.64万
-
财政年份:2010
-
负责人:Stephen T. McGarvey
-
依托单位:
Genome-Wide Association Studies of Adiposity in Samoans
-
批准号:8402646
-
项目类别:
-
资助金额:$73.68万
-
财政年份:2009
-
负责人:Stephen T. McGarvey
-
依托单位:
Genome-Wide Association Studies of Adiposity in Samoans
-
批准号:8598505
-
项目类别:
-
资助金额:$55.61万
-
财政年份:2009
-
负责人:Stephen T. McGarvey
-
依托单位:
Genome-Wide Association Studies of Adiposity in Samoans
-
批准号:8111680
-
项目类别:
-
资助金额:$80.77万
-
财政年份:2009
-
负责人:Stephen T. McGarvey
-
依托单位:
Genome-Wide Association Studies of Adiposity in Samoans
-
批准号:7922621
-
项目类别:
-
资助金额:$161.42万
-
财政年份:2009
-
负责人:Stephen T. McGarvey
-
依托单位:
Genome-Wide Association Studies of Adiposity in Samoans
-
批准号:7654549
-
项目类别:
-
资助金额:$141.33万
-
财政年份:2009
-
负责人:Stephen T. McGarvey
-
依托单位:
Diabetes Care in American Samoa
-
批准号:7287349
-
项目类别:
-
资助金额:$57.02万
-
财政年份:2006
-
负责人:Stephen T. McGarvey
-
依托单位:
Diabetes Care in American Samoa
-
批准号:7129138
-
项目类别:
-
资助金额:$63.61万
-
财政年份:2006
-
负责人:Stephen T. McGarvey
-
依托单位:
Diabetes Care in American Samoa
-
批准号:7657285
-
项目类别:
-
资助金额:$58.11万
-
财政年份:2006
-
负责人:Stephen T. McGarvey
-
依托单位:
Diabetes Care in American Samoa
-
批准号:7476348
-
项目类别:
-
资助金额:$56.99万
-
财政年份:2006
-
负责人:Stephen T. McGarvey
-
依托单位:
Diabetes Care in American Samoa
-
批准号:7459948
-
项目类别:
-
资助金额:$0.7万
-
财政年份:2006
-
负责人:Stephen T. McGarvey
-
依托单位:
Genetic modification of PUFA biosynthesis and CHD
-
批准号:7393827
-
项目类别:
-
资助金额:$60.66万
-
财政年份:2006
-
负责人:Stephen T. McGarvey
-
依托单位:
Puberty, Immunity and Malnutrition in S. Japonicum
-
批准号:6511530
-
项目类别:
-
资助金额:$60.73万
-
财政年份:2001
-
负责人:Stephen T. McGarvey
-
依托单位:
Puberty, Immunity and Malnutrition in S. Japonicum
-
批准号:6333087
-
项目类别:
-
资助金额:$51.73万
-
财政年份:2001
-
负责人:Stephen T. McGarvey
-
依托单位:
GENOME SCAN FOR OBESITY SUSCEPTIBILITY LOCI IN SAMOANS
-
批准号:6382012
-
项目类别:
-
资助金额:$58.05万
-
财政年份:2000
-
负责人:Stephen T. McGarvey
-
依托单位:
GENOME SCAN FOR OBESITY SUSCEPTIBILITY LOCI IN SAMOANS
-
批准号:6790033
-
项目类别:
-
资助金额:$34.54万
-
财政年份:2000
-
负责人:Stephen T. McGarvey
-
依托单位:
GENOME SCAN FOR OBESITY SUSCEPTIBILITY LOCI IN SAMOANS
-
批准号:6524506
-
项目类别:
-
资助金额:$57.45万
-
财政年份:2000
-
负责人:Stephen T. McGarvey
-
依托单位:
GENOME SCAN FOR OBESITY SUSCEPTIBILITY LOCI IN SAMOANS
-
批准号:6333943
-
项目类别:
-
资助金额:$55.71万
-
财政年份:2000
-
负责人:Stephen T. McGarvey
-
依托单位:
ECOLOGY AND TRANSMISSION OF S.JAPONICUM: PHILIPPINES
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批准号:6776435
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项目类别:
-
资助金额:$30.81万
-
财政年份:2000
-
负责人:Stephen T. McGarvey
-
依托单位:
ECOLOGY AND TRANSMISSION OF S.JAPONICUM: PHILIPPINES
-
批准号:6292451
-
项目类别:
-
资助金额:$38.09万
-
财政年份:2000
-
负责人:Stephen T. McGarvey
-
依托单位:
海外基金