Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
基本信息
- 批准号:10443753
- 负责人:
- 金额:$ 54.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-20 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdolescenceAdolescent obesityAffectAnimal ModelBehaviorBody CompositionBody WeightBrainBrain regionCandidate Disease GeneChildhoodChromosome MappingComplexConsumptionDataDependovirusDietDiseaseDissectionEatingEnergy MetabolismEnvironmentExposure toFastingFat-Restricted DietFatty acid glycerol estersFood EnergyFutureGene ExpressionGenesGeneticGenetic TechniquesGenomeGenomic SegmentGenomicsGenotypeGlucoseGlucose IntoleranceHealthHeritabilityHigh Fat DietHippocampus (Brain)HumanHuman GenomeHypothalamic structureInbreedingInsulinInsulin ResistanceLaboratoriesLeadLife StyleLightMapsMeasuresMediationMetabolicMetabolic DiseasesMetabolismModelingNeuraxisNeuronsObesityObesity EpidemicOutcomeOverweightPathway AnalysisPathway interactionsPhenotypePhysiologicalPlayPopulationPredispositionPrevalenceQuantitative Trait LociRattusRegulationResearch DesignRisk FactorsRodent ModelRoleRunningSystemTestingTissuesTranscriptWorkbrain tissuediet-induced obesitydietary controlfamily structuregene functiongene networkgenetic makeupgenome sequencinggenome wide association studygenomic locusglucose toleranceinsulin sensitivityknock-downnew therapeutic targetnovelobesity in childrenobesogenicoverexpressionresponsetooltraittranscriptometranscriptome sequencingwhole genome
项目摘要
Project Summary
Obesity is a complex disease, affected by genetics and the environment. Currently over one third of the US
population is obese and obesity prevalence in childhood and adolescence is increasing. Diet and lifestyle are
major environmental contributors to obesity. Recent work has shown that genetic make-up influences how we
respond to diet (e.g., not everyone on a high fat diet (HF) becomes obese) and human genome-wide
association studies point to the brain as the major tissue influencing obesity. Not surprisingly, brain function is
also altered by diet and influenced by genetics. Understanding the interplay between diet and genetics,
including its role in impacting brain function, adiposity, and metabolic health is essential for understanding
underlying physiological mechanisms. Such studies are challenging to conduct in human populations. The
central premise of this work is that genetic make-up influences response to obesogenic environments, such as
a HF diet, and that regulatory brain function plays a major role in this response. Our laboratory uses an
outbred rat model, heterogeneous stock (HS) rats, for genetic mapping of adiposity traits. HS rats were
created by combining eight inbred founder strains and maintaining them in a way that minimizes inbreeding.
We have shown that adiposity is heritable in the HS and have fine-mapped genetic loci and identified both
novel and known genes that underlie adiposity. Similar to human GWAS, many of the genes we have
identified act in the brain to alter adiposity. Our preliminary data indicates that some HS rats are protected
against the negative consequences of a HF diet and that this is likely driven by genetics. The current proposal
sets out to use HS rats to understand the interplay between genome, diet and brain transcriptome. The overall
hypothesis is that genetic make-up influences susceptibility to diet-induced obesity in HS rats and that this is,
in part, driven by altering the brain transcriptome. In Aim 1, we will identify genetic loci that underlie protection
from (or susceptibility to) diet-induced obesity in HS rats. In Aim 2, we will identify changes in the brain
(specifically hypothalamus and hippocampus) in response to a HF diet as well as map brain transcriptome
changes that interact with diet to drive metabolic outcomes in HS rats. We will also create gene networks that
respond to diet and influence adiposity. We will use a variety of statistical and genetic techniques, including
comparison to human genome wide association studies and the DIETFITS trial, to identify high priority
candidate genes which will then be verified using adeno-associated virus over-expression or knock-down,
followed by phenotyping to begin to understand underlying gene function. We expect that this work will not
only shed light on genetic drivers that lead to protection from the negative consequences of a HF diet, but will
also elucidate interactions between diet, genome and brain transcriptome in altering metabolic health.
Because this proposal is focused on the central nervous system, we expect that many of these drivers will
serve as novel therapeutic targets to impact human behavior, a central feature in the obesity epidemic.
项目摘要
肥胖是一种复杂的疾病,受遗传和环境的影响。目前,超过三分之一的美国
人口肥胖,儿童和青少年肥胖症流行率正在增加。饮食和生活方式
肥胖的主要环境因素。最近的研究表明,基因构成影响我们如何
对饮食有反应(例如,并不是每个高脂肪饮食(HF)的人都会变得肥胖),
相关研究指出,大脑是影响肥胖的主要组织。毫不奇怪,大脑功能
也受饮食和遗传的影响。了解饮食和遗传之间的相互作用,
包括它在影响大脑功能、肥胖和代谢健康方面的作用,
潜在的生理机制在人群中进行此类研究具有挑战性。的
这项工作的中心前提是,遗传组成影响对致胖环境的反应,如
HF饮食,并且调节脑功能在这种反应中起主要作用。我们的实验室使用
远交大鼠模型,异质性股票(HS)大鼠,肥胖性状的遗传作图。HS大鼠
通过结合八个近亲繁殖的创始人菌株,并以最小化近亲繁殖的方式保持它们。
我们已经证明了肥胖在HS中是可遗传的,并且已经精细定位了遗传位点,
新的和已知的肥胖基因。与人类GWAS相似,我们拥有的许多基因
在大脑中发现了改变肥胖的作用。我们的初步数据表明,一些HS大鼠受到保护,
对抗HF饮食的负面影响,这可能是由遗传学驱动的。现时的建议
开始使用HS大鼠来了解基因组,饮食和大脑转录组之间的相互作用。整体
假设遗传组成影响HS大鼠对饮食诱导的肥胖的易感性,
部分是由改变大脑转录组驱动的。在目标1中,我们将确定作为保护基础的遗传位点
从(或易感性)饮食诱导的肥胖HS大鼠。在目标2中,我们将识别大脑中的变化
(特别是下丘脑和海马)对HF饮食的反应以及映射脑转录组
这些变化与饮食相互作用,以驱动HS大鼠的代谢结果。我们还将创建基因网络,
对饮食做出反应并影响肥胖。我们将使用各种统计和遗传技术,包括
与人类全基因组关联研究和DIETFITS试验进行比较,以确定高优先级
然后将使用腺相关病毒过表达或敲低来验证候选基因,
然后进行表型分析,开始了解潜在的基因功能。我们希望这项工作不会
这只揭示了导致保护免受HF饮食负面影响的遗传驱动因素,但将
还阐明了饮食,基因组和大脑转录组在改变代谢健康之间的相互作用。
因为这项建议是集中在中枢神经系统,我们预计,许多这些司机将
作为影响人类行为的新的治疗靶点,这是肥胖流行病的一个中心特征。
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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Leah Catherine Solberg Woods其他文献
Leah Catherine Solberg Woods的其他文献
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{{ truncateString('Leah Catherine Solberg Woods', 18)}}的其他基金
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10646341 - 财政年份:2019
- 资助金额:
$ 54.58万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10194486 - 财政年份:2019
- 资助金额:
$ 54.58万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
9914686 - 财政年份:2019
- 资助金额:
$ 54.58万 - 项目类别:
Systems genetics to identify neuronal genes for diet-induced obesity
系统遗传学识别饮食引起的肥胖的神经元基因
- 批准号:
10020972 - 财政年份:2019
- 资助金额:
$ 54.58万 - 项目类别:
Systems Genetics of Adiposity Traits in Outbred Rats
远交大鼠肥胖性状的系统遗传学
- 批准号:
9145731 - 财政年份:2015
- 资助金额:
$ 54.58万 - 项目类别:
Systems Genetics of Adiposity Traits in Outbred Rats
远交大鼠肥胖性状的系统遗传学
- 批准号:
9421356 - 财政年份:2015
- 资助金额:
$ 54.58万 - 项目类别:
Center for Genetic Studies of Drug Abuse in Outbred Rats
近交系大鼠药物滥用基因研究中心
- 批准号:
10160844 - 财政年份:2014
- 资助金额:
$ 54.58万 - 项目类别:
Center for Genetic Studies of Drug Abuse in Outbred Rats
近交系大鼠药物滥用基因研究中心
- 批准号:
10613525 - 财政年份:2014
- 资助金额:
$ 54.58万 - 项目类别:
Center for Genetic Studies of Drug Abuse in Outbred Rats
近交系大鼠药物滥用基因研究中心
- 批准号:
10402307 - 财政年份:2014
- 资助金额:
$ 54.58万 - 项目类别:
Genome-wide fine-mapping of metabolic traits in heterogeneous stock rats
异种大鼠代谢特征的全基因组精细图谱
- 批准号:
8469856 - 财政年份:2010
- 资助金额:
$ 54.58万 - 项目类别:
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