Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
基本信息
- 批准号:10619310
- 负责人:
- 金额:$ 13.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Project Summary
Over the last 30 years, diabetes has become a pandemic. Type 2 diabetes is the most common form of
diabetes, and pancreatic β cell failure is pivotal in the pathogenesis of this metabolic disorder. Restoring β cell
function has taken center stage in developing therapeutics to “cure” diabetes, through inducing β cell
proliferation, re-differentiation, and regeneration. However, the quality and quantity of “β cell” obtained are less
than ideal. One critical aspect to facilitate these processes to generating “perfect” β cell is to understand the
epigenetic changes involved in β cell formation and maintenance. More and more evidence suggests that
histone modification and chromatin remodeling play critical roles in β cell development, cell fate commitment,
proliferation, and regeneration. Key β cell transcription factor FoxO1 is required to maintain β cell maturity.
Ablation of FoxO1 in β cells leads to β cell dedifferentiation, a process where mature β cells lose their identity
and ability to produce and secret insulin. In healthy β cells, FoxO1 is inactive and resides in the cytoplasm. In
response to stressors, such as aging and multiparity, FoxO1 translocates into the nucleus, and elicits
transcriptional networks to defend β cell health. In advanced type 2 diabetes, FoxO1 disappears from β cells
as a result of increased degradation, leading to metabolic inflexibility and paving the way for dedifferentiation.
However, whether the protective role of FoxO1 against β cell failure involves maintaining the epigenomic
landscape has not been studied. The proposed studies will fill the gap of knowledge between FoxO1,
epigenetics, functional genomics, and diabetes. The PI presented preliminary data to establish a role of FoxO1
in epigenetics with RNAseq and histone modification ChIPseq (i.e., H3K4me3, H3K27me3, and H3K27ac)
using FAC sorted β cells in β cell-specific FoxO1 KO mice. The PI will continue to build the integrative
regulatory map of FoxO1 in pancreatic β-cell with Hi-C, DNA methylation, and FoxO1 ChIPseq. H3K27ac motif
analysis and RNA profiling suggest an imbalanced regulation between FoxO1 and Hnf4α, therefore, the PI will
perform glucose clamps, glucose tolerance test, glucose- and arginine-stimulated insulin secretion in isolated
islets, and RNAseq using β cell-specific FoxO1 and Hnf4α double KO mice to determine the epistasis of
FoxO1 and Hnf4α. The PI will also functionally characterize FoxO1 targets to identify genes of therapeutic
interest. The tailored research training and career development activities will assist the PI to achieve her career
goals: becoming an independent academic investigator and advancing the field of diabetes research.
项目摘要
在过去的30年里,糖尿病已经成为一种流行病。2型糖尿病是最常见的糖尿病类型。
糖尿病和胰腺β细胞衰竭在这种代谢紊乱的发病机制中是关键的。恢复β细胞
在开发“治愈”糖尿病的疗法中,通过诱导β细胞,
增殖、再分化和再生。但所获得的“β细胞”质和量均较少
比理想。促进这些过程以产生“完美的”β细胞的一个关键方面是理解细胞的功能。
表观遗传变化参与β细胞的形成和维持。越来越多的证据表明,
组蛋白修饰和染色质重塑在β细胞发育、细胞命运定型
增殖和再生。关键β细胞转录因子FoxO 1是维持β细胞成熟所必需的。
β细胞中FoxO 1的消融导致β细胞去分化,这是成熟β细胞失去其身份的过程
和分泌胰岛素的能力。在健康的β细胞中,FoxO 1是无活性的,存在于细胞质中。在
在对应激源的反应中,如衰老和多胎,FoxO 1易位到细胞核中,
转录网络来保护β细胞的健康。在晚期2型糖尿病中,FoxO 1从β细胞中消失
由于降解增加,导致代谢不稳定,并为去分化铺平道路。
然而,FoxO 1对β细胞衰竭的保护作用是否涉及维持表观基因组
景观还没有研究过。拟议的研究将填补FoxO 1,
表观遗传学、功能基因组学和糖尿病。PI提供了初步数据,以确定FoxO 1的作用
在具有RNAseq和组蛋白修饰ChIPseq的表观遗传学中(即,H3 K4 me 3、H3 K27 me 3和H3 K27 ac)
在β细胞特异性FoxO 1 KO小鼠中使用FAC分选的β细胞。PI将继续建立一体化的
用Hi-C、DNA甲基化和FoxO 1 ChIPseq在胰腺β细胞中的FoxO 1调控图谱。H3 K27 ac基序
分析和RNA分析表明FoxO 1和Hnf 4 α之间的调节不平衡,因此,PI将
进行葡萄糖钳夹,葡萄糖耐量试验,葡萄糖和精氨酸刺激的胰岛素分泌,
胰岛,并使用β细胞特异性FoxO 1和Hnf 4 α双KO小鼠进行RNA测序以确定
FoxO 1和Hnf 4 α。PI还将对FoxO 1靶点进行功能表征,以鉴定治疗基因。
兴趣量身定制的研究培训和职业发展活动将帮助PI实现其职业生涯
目标:成为独立的学术研究者,推进糖尿病研究领域。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Taiyi Diana Kuo其他文献
Taiyi Diana Kuo的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Taiyi Diana Kuo', 18)}}的其他基金
Decipher the Function of C2cd4a in Metabolism
解读 C2cd4a 在代谢中的功能
- 批准号:
10594862 - 财政年份:2023
- 资助金额:
$ 13.85万 - 项目类别:
Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
- 批准号:
10179361 - 财政年份:2018
- 资助金额:
$ 13.85万 - 项目类别:
Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
- 批准号:
10435937 - 财政年份:2018
- 资助金额:
$ 13.85万 - 项目类别:
Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
- 批准号:
9599028 - 财政年份:2018
- 资助金额:
$ 13.85万 - 项目类别:
相似海外基金
Determining the role of WT and mutant FOXO1 in the transcriptional regulation of DLBCL
确定 WT 和突变体 FOXO1 在 DLBCL 转录调控中的作用
- 批准号:
10450635 - 财政年份:2021
- 资助金额:
$ 13.85万 - 项目类别:
Determining the role of WT and mutant FOXO1 in the transcriptional regulation of DLBCL
确定 WT 和突变体 FOXO1 在 DLBCL 转录调控中的作用
- 批准号:
10617282 - 财政年份:2021
- 资助金额:
$ 13.85万 - 项目类别:
Regulation of lymphangiogenesis targeting FOXO1-xCT anti-oxidative stress pathway
针对 FOXO1-xCT 抗氧化应激通路的淋巴管生成调控
- 批准号:
19K16481 - 财政年份:2019
- 资助金额:
$ 13.85万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
- 批准号:
10179361 - 财政年份:2018
- 资助金额:
$ 13.85万 - 项目类别:
Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
- 批准号:
10435937 - 财政年份:2018
- 资助金额:
$ 13.85万 - 项目类别:
Epigenetic Regulation by FoxO1 in Pancreatic Beta Cells
FoxO1 在胰腺 Beta 细胞中的表观遗传调控
- 批准号:
9599028 - 财政年份:2018
- 资助金额:
$ 13.85万 - 项目类别:
Hypothalamic Sirt1 and FoxO1 in energy balance regulation
下丘脑 Sirt1 和 FoxO1 在能量平衡调节中的作用
- 批准号:
25460310 - 财政年份:2013
- 资助金额:
$ 13.85万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Role of FoxO1 in the Regulation of the Adipocyte Browning Response
FoxO1 在脂肪细胞褐变反应调节中的作用
- 批准号:
8705254 - 财政年份:2013
- 资助金额:
$ 13.85万 - 项目类别:
The Role of FoxO1 in the Regulation of the Adipocyte Browning Response
FoxO1 在脂肪细胞褐变反应调节中的作用
- 批准号:
8913161 - 财政年份:2013
- 资助金额:
$ 13.85万 - 项目类别:
The Role of FoxO1 in the Regulation of the Adipocyte Browning Response
FoxO1 在脂肪细胞褐变反应调节中的作用
- 批准号:
8591503 - 财政年份:2013
- 资助金额:
$ 13.85万 - 项目类别: