Human hypothalamic neuronal epigenomics and risk for obesity
人类下丘脑神经元表观基因组学和肥胖风险
基本信息
- 批准号:10836243
- 负责人:
- 金额:$ 38.94万
- 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:2023-05-03 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
ABSTRACT
Translating information on genetic risk for body weight regulation into molecular mechanisms can
have a significant impact on intervention and therapies. We are seeking to identify genetic variation
and their molecular mechanisms that influences obesity through direct effects on the hypothalamus as it
is the brain hub that regulates energy homeostasis and there is now considerable evidence for genetic
influence to impact this brain region. However, the majority of genetic loci associated with this common,
chronic disorder in the general population are located in noncoding regions of the genome, suggesting
their influence on energy homeostasis is manifested through changes to the regulome. Thus, pinpointing
the causal human variants and connecting them to their downstream targets in brain presents
challenges of tissue access for study because much epigenetic control is species-, tissue- and context-
specific. To overcome the barrier of limited human tissue access, we have developed a robust protocol
for generating human induced pluripotent stem cell (iPSC)- derived neuronal cultures that recapitulate
many of the features of hypothalamic neurons from the arcuate nucleus, including by benchmarking
this in vitro model to in vivo events that are pivotal in hypothalamic development. We are using this
human model and state of the art high throughput assays to map the currently uncharted regulatory
landscape of the human hypothalamic neurons across 3 stages in development (early, mid, and late)
and under experimental obesogenic conditions. We have published an integrated pipeline to chart the
regulatory landscapes of obesity-associated loci within two cell types central to obesity etiology. Next,
in order to precisely pinpoint the functional variants in BMI GWAS loci that have influence on body weight
regulation through hypothalamic epigenomic regulation, we will identify those that influence chromatin
accessibility and/or target gene expression by assay in 30 iPSC-derived hypothalamic-like cellular models
generated from subjects of the San Antonio Mexican American Family Studies. GWAS variants with
both properties have high potential to be causal and manifest effects on body mass index through
changes in chromatin structure. Causal determination will be made for a set of these variants using
genome editing techniques such as CRISPR/Cas9 to generate isogenic human neuronal cell lines that
differ by genotype only at the single locus. Changes in exon-specific target gene expression and
chromatin status will be assessed temporally and under each obesogenic condition. Discovery of
epigenetic mechanisms connected to genetic liability will translate the genetic risk information and identify
potential underlying factors behind both heritable and diet-induced obesity susceptibility.
摘要
将体重调节的遗传风险信息转化为分子机制,
对干预和治疗有重大影响。我们在寻找基因变异
以及它们通过直接作用于下丘脑而影响肥胖的分子机制,
是调节能量稳态的大脑中枢,现在有相当多的证据表明,
影响这个大脑区域。然而,大多数与这种常见的,
一般人群中的慢性疾病位于基因组的非编码区,这表明
它们对能量稳态的影响通过调节组的变化而显现。因此,
因果人类变异并将它们与大脑中的下游目标联系起来,
组织获取研究的挑战,因为许多表观遗传控制是物种,组织和背景,
特定.为了克服有限的人体组织获取的障碍,我们开发了一个强大的协议,
用于产生人诱导多能干细胞(iPSC)衍生的神经元培养物,
弓状核的下丘脑神经元的许多特征,包括通过基准
将这种体外模型应用于下丘脑发育中关键的体内事件。我们正在使用这
人类模型和最先进的高通量测定,以绘制目前未知的调控基因,
人类下丘脑神经元在3个发育阶段(早期、中期和晚期)的景观
在实验性致肥胖条件下。我们已经发布了一个综合管道,
肥胖病因学中心的两种细胞类型内肥胖相关基因座的调节景观。接下来,
为了精确定位BMI GWAS基因座中影响体重的功能变异,
通过下丘脑表观基因组调控,我们将确定那些影响染色质
在30个iPSC衍生的下丘脑样细胞模型中通过测定的可及性和/或靶基因表达
来自圣安东尼奥墨西哥裔美国人家庭研究的主题。GWAS变体,
这两种性质都有很高的可能性是因果关系,并通过以下方式对体重指数产生明显影响:
染色质结构的变化。将使用以下方法确定一组这些变体的因果关系
基因组编辑技术如CRISPR/Cas9来产生等基因人类神经元细胞系,
不同基因型只在一个基因座。外显子特异性靶基因表达的变化,
染色质状态将在时间上和在每种致肥胖条件下进行评估。发现
与遗传责任相关的表观遗传机制将翻译遗传风险信息,
遗传和饮食诱导的肥胖易感性背后的潜在因素。
项目成果
期刊论文数量(0)
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{{ truncateString('DONNA M LEHMAN', 18)}}的其他基金
Human hypothalamic neuronal epigenomics and risk for obesity
人类下丘脑神经元表观基因组学和肥胖风险
- 批准号:
9596999 - 财政年份:2018
- 资助金额:
$ 38.94万 - 项目类别:
Human hypothalamic neuronal epigenomics and risk for obesity
人类下丘脑神经元表观基因组学和肥胖风险
- 批准号:
10207613 - 财政年份:2018
- 资助金额:
$ 38.94万 - 项目类别:
Metformin, Statins, and Prostate Cancer Prevention in Type 2 Diabetes
二甲双胍、他汀类药物和 2 型糖尿病的前列腺癌预防
- 批准号:
8539478 - 财政年份:2012
- 资助金额:
$ 38.94万 - 项目类别:
Metformin, Statins, and Prostate Cancer Prevention in Type 2 Diabetes
二甲双胍、他汀类药物和 2 型糖尿病的前列腺癌预防
- 批准号:
8303675 - 财政年份:2012
- 资助金额:
$ 38.94万 - 项目类别:
Type 2 Diabetes Gene Discovery Linked to 3p in Hispanics
西班牙裔 2 型糖尿病基因发现与 3p 相关
- 批准号:
7636833 - 财政年份:2007
- 资助金额:
$ 38.94万 - 项目类别:
Type 2 Diabetes Gene Discovery Linked to 3p in Hispanics
西班牙裔 2 型糖尿病基因发现与 3p 相关
- 批准号:
7477192 - 财政年份:2007
- 资助金额:
$ 38.94万 - 项目类别:
Type 2 Diabetes Gene Discovery Linked to 3p in Hispanics
西班牙裔 2 型糖尿病基因发现与 3p 相关
- 批准号:
7319458 - 财政年份:2007
- 资助金额:
$ 38.94万 - 项目类别:
Type 2 Diabetes Gene Discovery Linked to 3p in Hispanics
西班牙裔 2 型糖尿病基因发现与 3p 相关
- 批准号:
7769760 - 财政年份:2007
- 资助金额:
$ 38.94万 - 项目类别:
NIDDM Susceptibility Genes in Mexican Americans
墨西哥裔美国人的 NIDDM 易感基因
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7916492 - 财政年份:1993
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$ 38.94万 - 项目类别:
NIDDM Susceptibility Genes in Mexican Americans
墨西哥裔美国人的 NIDDM 易感基因
- 批准号:
7487910 - 财政年份:1993
- 资助金额:
$ 38.94万 - 项目类别:
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