The DNA methylome-based regulation of functional beta-cell mass
The DNA methylome-based regulation of functional beta-cell mass
批准号:
10287569
负责人:
Guoqiang Gu
金额:
$39.61万
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
项目状态:
未结题
起止时间:
2020-07-01 至 2025-06-30
关键词:
AdultAffectAgeAge-MonthsAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAttenuatedB cell differentiationB-Lymphocyte SubsetsBehavioral AssayBeta CellBiological AssayBrainBrain regionCandidate Disease GeneCell SurvivalCell physiologyCellsCessation of lifeDNADNA MethylationDNA Modification MethylasesDNMT3aDataDeteriorationDevelopmentDiseaseEmbryoEndocrineEnhancersEpigenetic ProcessExposure toFetal DevelopmentFoundationsFunctional disorderGenesGoalsHaplotypesHealthHippocampus (Brain)HumanHypothalamic structureImmunoassayImmunocompromised HostImpairmentInstructionIslet CellIslets of LangerhansLearningLinkMemoryMetabolic stressMethylationModelingMolecularMusNeuronsNon-Insulin-Dependent Diabetes MellitusPancreasParentsPatternPhenotypePhysiologicalProductionProtein-Restricted DietPublishingRecording of previous eventsRegulationRiskSentinelTechniquesTestingTissuesallotransplantbasebrain celldiabeticdosagefitnessfitness testgene functiongenome-wideimprovedisletislet stem cellsmethylation patternmethylomemouse Neurog3 proteinmouse modelnerve stem celloffspringpostnatalprogenitorprogramsresponsestem cellssynaptotagmin VIItau Proteinstranscription factortranscriptome
中文摘要
此补充剂应用程序旨在测试母亲在胎儿发育过程中如何暴露于低蛋白饮食
影响生后小鼠下丘脑和海马神经元的功能和活性。这个
假说是宫内因素调节胚胎神经前体细胞的DNA甲基组;
这种甲基化模式预先决定了关键神经元基因的表达水平,因此预设了
成人阿尔茨海默病及相关疾病的风险(ADRD)。具体地说,我们将重点关注
神经细胞来源于胚胎祖细胞,表达转录因子神经原3(又名。
Neurog3或Ngn3)。已发表的研究表明,这些Ngn3+前体细胞在
下丘脑和海马体,其功能恶化与ADRD密切相关。因此,我们将
小鼠脑内分离纯化胚胎Ngn3+神经前体细胞及其成体后代
检查这些细胞的甲基组和转录组。这些模式将被直接比较
对照组小鼠和那些接触母体低蛋白饮食的小鼠。此外,一些关键候选人的免疫分析
将进行的基因,包括Syt1,Syt7,APP和Tau,对神经元功能和相关的
分别与ADRD合作。我们的初步数据显示DNA对这两个候选人的调控
甲基化证明这些检测是正确的。基本的行为分析也将被用来关联生理上的
DNA甲基化状态的表型。值得注意的是,这些研究与将在
亲本R01的目标3,它检查了宫内因素如何影响
NGN3+胰岛β细胞前体细胞及其成年后代在2型糖尿病(T2D)背景下的功能。
因此,这些补充研究依赖于相同的小鼠模型、相同的技术和相似的专业知识
与父R01中建议的相同。更重要的是,人们早就认识到,T2D和ADRD是
这两种疾病的风险都受到宫内病史的严重影响。因此,
研究在Ngn3+谱系的发展/功能中重叠和不同的机制,其中之一
胰腺是大脑中的另一种器官,预计会产生潜在的靶点来干扰两者的发育
疾病。
英文摘要
This supplement application aims to test how maternal low-protein diet exposure during fetal development
impacts the function and viability of neurons in postnatal mouse hypothalamus and hippocampus. The
hypothesis is that intrauterine factors modulate the DNA methylomes of embryonic neuronal progenitor cells;
this methylation pattern predetermines the expression levels of key neuronal genes and therefore preset the
risk of Alzheimer’s diseases and related diseases (ADRD) in adult ages. Specifically, we will focus on the
neurons that are derived from embryonic progenitor cells that express transcription factor Neurogenin 3 (a.k.a.
Neurog3 or Ngn3). Published studies have shown that these Ngn3+ progenitors give rise to neurons in the
hypothalamus and hippocampus, whose deteriorating function is closely associated with ADRD. Thus, we will
purify embryonic Ngn3+ neural progenitor cells as well as their adult descendants in mouse brains and
examine the methylome and transcriptome of these cells. These patterns will be directly compared between
control mice and those exposed to maternal low-protein diet. In addition, immunoassays in some key candidate
genes will be conducted, including Syt1, Syt7, APP, and Tau, important for neuronal function and associated
with ADRD, respectively. Our preliminary data showing the regulation of these two candidates by DNA
methylation justify these assays. Basic behavioral assays will also used to correlate the physiological
phenotype with the DNA methylation states. Notably, these studies are parallel to what will be pursued in the
Aim 3 of the parent R01, which examines how intrauterine factors impact the methylomes/transcriptomes of
Ngn3+ islet beta-cell progenitors and the function of their adult progeny in the context of type 2 diabetes (T2D).
These supplement studies therefore rely on identical mouse models, same techniques, and similar expertise
as those proposed in the parent R01. More importantly, it has long been recognized that T2D and ADRD are
tightly linked with each other; the risks of both diseases are heavily affected by the intrauterine history. Thus,
examining the overlapping and distinct mechanisms in the development/function of Ngn3+ lineages, one in the
pancreas the other in the brain, is expected to yield potential targets to interfere with the development both
diseases.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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The Mechanisms of Islet Cell Specification and Differentiation
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海外基金