Gene regulatory mechanisms connecting metabolism and Alzheimer’s Disease
连接新陈代谢和阿尔茨海默病的基因调控机制
基本信息
- 批准号:10660149
- 负责人:
- 金额:$ 230.73万
- 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:2023-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAccidentsAdultAffectAge YearsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmericanApolipoprotein EAreaBehaviorBehavioralBiochemicalBrainCell NucleusCessation of lifeChIP-seqChromatinChromiumDiseaseDisease ProgressionEpidemicEpigenetic ProcessFastingFemaleFoundationsFutureGene ClusterGene ExpressionGenesGeneticGenomeGliosisGoalsHumanHuman BiologyHypothalamic structureIn Situ HybridizationInflammationKnock-outKnockout MiceLigationLinkMedicalMetabolicMetabolic DiseasesMetabolic PathwayMetabolic syndromeMetabolismModelingModificationMusNatureNerve DegenerationNeurodegenerative DisordersPathologyPhenotypeProcessPublic HealthRNARegulator GenesRegulatory ElementResearchRoleSenile PlaquesSignal TransductionSleepSocial supportStressSymptomsTestingTherapeuticTissuesblood glucose regulationcell typechromatin immunoprecipitationdisorder controlfeedingimprovedinnovationmalemouse modelmultiple omicsneuron lossnovelpreventresponserisk variantsingle-cell RNA sequencingtranscriptome sequencing
项目摘要
By 2050, Alzheimer's disease (AD) will be an epidemic affecting 13.8 million Americans, who will need ongoing
medical and social support. There is an urgent need to find mechanisms that can slow or prevent the disease.
Metabolism, epigenetics and gene expression have important roles in AD. Metabolic pathways directly regulate
biochemical modifications to chromatin at cis-regulatory elements (CREs) that control gene expression.
Therefore, specific CREs could be a critical interface between metabolism, gene expression and AD. However,
there are millions of CREs in the genome and finding primary CREs for functional studies is a challenge. Our
study will define an important new subclass of CRE that affects AD pathology and regulates
connections between metabolism, gene expression and AD processes. In unpublished studies, we
developed an innovative H3K27ac-targeted paired PLAC-Seq + RNASeq (pPR-Seq) approach to
simultaneously profile active CREs, cis-regulatory contacts and gene expression in tissues. For the adult
mouse hypothalamus, we uncovered super-looping CREs that form contacts with multiple neighboring genes,
and function to coordinate gene co-expression. We call these coordinator CREs (cCREs). We found that
cCREs make up 18% of hypothalamic CREs and are significantly enriched at AD risk genes and genes
responsive to metabolic changes compared to canonical CREs that regulate single genes. In knockout (KO)
mice for one cCRE, we found significant gene expression, metabolic response, behavioral and aging
phenotypes. The hypothalamus is an important new area of focus in AD. Others have proposed that early
neurodegenerative changes in the hypothalamus contribute to cascading metabolic and homeostatic
dysregulation that drives AD progression. Our study builds on this idea with a focus on cCREs. Currently, we
do not fully understand the functions of hypothalamic cCREs or how cCREs linked to AD risk genes affect AD
brain and behavioral pathology. Moreover, nature of cCREs in the human hypothalamus is unknown. Here, we
test the general hypothesis that hypothalamic cCREs are regulatory hubs that disproportionately integrate
metabolic and neurodegeneration signals compared to canonical CREs, and regulate the co-expression of
neighboring genes, affect the progression AD pathology in mouse models and show conservation between
mice and humans. Aim 1 will determine how chromatin accessibility changes at cCREs in response to
metabolic and neurodegeneration signals in mice and define the cell-types that different cCREs are active in.
Aim 2 will determine the functions of cCREs regulating important AD risk loci, including Abca7, Picalm and
Fto-Irx, and effects on AD pathology in 5xFAD mice. Aim 3 will uncover cCREs in the human hypothalamus
and determine conservation with mice. In summary, our study will define conserved hypothalamic cCREs that
function as important cis-regulatory hubs connecting metabolic and AD processes. By understanding these
fundamental new mechanisms that affect primary AD risk genes and processes, future studies will be able to
study cCREs in human AD and devise strategies to modify cCRE activity to slow AD progression.
到2050年,阿尔茨海默病(AD)将成为一种流行病,影响1380万美国人,他们将需要继续治疗
项目成果
期刊论文数量(0)
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Chris Gregg其他文献
Chris Gregg的其他文献
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{{ truncateString('Chris Gregg', 18)}}的其他基金
Functions and Mechanisms of Epigenetic Allelic Effects in the Brain
大脑表观遗传等位基因效应的功能和机制
- 批准号:
9807101 - 财政年份:2019
- 资助金额:
$ 230.73万 - 项目类别:
The Nature and Function of Genomic Imprinting in Monoaminergic Neurons
单胺能神经元基因组印记的性质和功能
- 批准号:
10367506 - 财政年份:2016
- 资助金额:
$ 230.73万 - 项目类别:
The Nature and Function of Genomic Imprinting in Monoaminergic Neurons
单胺能神经元基因组印记的性质和功能
- 批准号:
10491164 - 财政年份:2016
- 资助金额:
$ 230.73万 - 项目类别:
The Nature and Function of Genomic Imprinting in Monoaminergic Neurons
单胺能神经元基因组印记的性质和功能
- 批准号:
9079842 - 财政年份:2016
- 资助金额:
$ 230.73万 - 项目类别:
The Nature and Function of Genomic Imprinting in Monoaminergic Neurons
单胺能神经元基因组印记的性质和功能
- 批准号:
10693307 - 财政年份:2016
- 资助金额:
$ 230.73万 - 项目类别:
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