Epigenetic determinants of beta cell development and function

β细胞发育和功能的表观遗传决定因素

基本信息

批准号：
10672331
负责人：
Matthew Wortham
金额：
$ 46.41万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672331
关键词：
Acceleration Acute Affect Beta Cell Caloric Restriction Cell Line Cell physiology Cells Chromatin Chronic Collection Compensation Computer Analysis Cues Diabetes Mellitus Environment Epigenetic Process Exhibits Failure Functional disorder Funding Gene Expression Genes Genetic Genetic Transcription Glucose Goals Grant Histone Acetylation Histone Deacetylase Hormones Human In Vitro Insulin KDM1A gene Link Lipids Maps Measures Mediating Metabolic Metabolic stress Modeling Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Output Overnutrition Pathway interactions Phenotype Physiological Plasma Prediabetes syndrome Process Proliferating Regulation Regulator Genes Regulatory Element Resolution Role Signal Transduction Stimulus Structure of beta Cell of islet Testing Therapeutic Thinness Translating Transplantation cofactor detection of nutrient endocrine pancreas development epigenome epigenomics experimental study feeding functional adaptation glucose metabolism histone demethylase histone methylation improved in vivo insight insulin regulation insulin secretion islet mouse model non-diabetic novel prevent programs recruit response scaffold transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT Insulin produced by pancreatic β-cells is the key stimulus for glucose metabolism, and therefore it is critical that insulin secretion is adjusted to changes in energy state. Insulin secretion is acutely regulated by nutrients and hormones that change in response to feeding. If the fed state persists, as in overnutrition, adaptive control mechanisms increasingly sensitize the insulin secretory response to meet the increased insulin demand. However, long-term overnutrition can also become maladaptive and lead to β-cell failure and type 2 diabetes (T2D). How β-cells read nutrient signals and translate these signals into adaptive and maladaptive responses is poorly understood. Supported by this grant, we have shown that the nutrient-sensitive histone demethylase LSD1 mediates nutrient-induced changes to the β-cell epigenome to regulate adaptative insulin secretion. Specifically, we found that LSD1 modifies the epigenetic state of gene regulatory elements linked to β-cell nutrient response genes, thereby modulating the amplitude of the insulin secretory response. Thus, LSD1 functions as an integration hub between the β-cell’s nutrient environment, the epigenome and transcriptional output. Our preliminary studies further show that LSD1 inhibition is adaptive in a lean state, but becomes maladaptive and promotes β-cell failure in obesity. The objective of this proposal is to determine the mechanisms by which LSD1 senses nutrients and to gain insight into how metabolic cues converge on LSD1 and the epigenome to render the adaptive β-cell response maladaptive. We will employ state-of-the-art approaches, encompassing novel mouse models, human islet experiments, single cell resolved mapping of chromatin state and gene expression, and cutting-edge computational analyses. In Aim 1, we will determine how LSD1 senses nutrients and regulates chromatin state in β-cells. To investigate the nutrient sensing mechanism, we will manipulate LSD1’s metabolically regulated co-factor FAD and measure effects on LSD1- regulated processes in β-cells. Furthermore, we will dissect LSD1’s enzymatic and non-enzymatic functions in regulating the β-cell epigenome, using novel mouse models and in vitro experiments. In Aim 2, we will identify mechanisms by which LSD1 inhibition triggers maladaptive processes that accelerate β-cell decompensation in T2D. Employing genetic mouse and islet models of metabolic stress, we will manipulate LSD1 activity and study how these manipulations affect β-cell chromatin state, gene expression, and phenotypes. In Aim 3, we will examine the role of LSD1 in human β-cells. Here, we will leverage transcriptomic and chromatin maps we generated from a collection of nondiabetic, prediabetic, and T2D donor islets to determine whether the LSD1- regulated program contributes to β-cell failure in T2D. By unveiling fundamental mechanisms by which β-cells interpret nutrient signals, this proposal will prove critical for identifying strategies to prevent or reverse maladaptive processes and β-cell failure.

项目概要/摘要胰腺β细胞产生的胰岛素是葡萄糖代谢的关键刺激物，因此至关重要胰岛素分泌根据能量状态的变化进行调整胰岛素分泌受到营养物质的强烈调节。如果进食状态持续存在，如营养过剩，适应性控制就会发生变化。机制使胰岛素分泌反应变得更加敏感，以满足增加的胰岛素需求。然而，长期营养过剩也会导致适应不良，导致 β 细胞衰竭和 2 型糖尿病 (T2D)。β 细胞如何读取营养信号并将这些信号转化为适应性和适应不良反应。在这项资助的支持下，我们已经证明了营养敏感的组蛋白去甲基化酶。 LSD1 介导营养诱导的 β 细胞表观基因组变化，以调节适应性胰岛素分泌。具体来说，我们发现 LSD1 改变与 β 细胞相关的基因调控元件的表观遗传状态营养反应基因，从而调节胰岛素分泌反应的幅度，因此，LSD1。作为 β 细胞营养环境、表观基因组和转录组之间的整合中心我们的初步研究进一步表明，LSD1 抑制在瘦状态下是适应性的，但会变得更少。适应不良并促进肥胖中的 β 细胞衰竭。 LSD1 感知营养物质的机制，并深入了解代谢线索如何汇聚到 LSD1 上和表观基因组使适应性β细胞反应适应不良我们将采用最先进的技术。方法，包括新颖的小鼠模型、人类胰岛实验、单细胞解析的图谱在目标 1 中，我们将确定染色质状态和基因表达以及尖端计算分析。 LSD1 如何感知营养并调节 β 细胞中的染色质状态研究营养感知。机制，我们将操纵 LSD1 的代谢调节辅因子 FAD 并测量对 LSD1 的影响- 此外，我们将剖析 LSD1 的酶促和非酶促功能。在目标 2 中，我们将使用新型小鼠模型和体外实验来调节 β 细胞表观基因组。 LSD1 抑制引发适应不良过程，加速 β 细胞失代偿的机制在 T2D 中，我们将利用代谢应激的遗传小鼠和胰岛模型来操纵 LSD1 活性并在目标 3 中，我们研究这些操作如何影响 β 细胞染色质状态、基因表达和表型。我们将研究 LSD1 在人类 β 细胞中的作用，我们将利用转录组和染色质图谱。从一组非糖尿病、糖尿病前期和 T2D 供体胰岛中生成，以确定 LSD1- 调控程序通过揭示 β 细胞的基本机制导致 T2D 中的 β 细胞衰竭。解释营养信号，该提案对于确定预防或逆转策略至关重要适应不良过程和β细胞衰竭。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

NKX6 transcription factor activity is required for alpha- and beta-cell development in the pancreas.

NKX6 转录因子活性是胰腺 α 和 β 细胞发育所必需的。

DOI：
发表时间：
2005-07
期刊：
影响因子：
0
作者：
Henseleit, Korinna D;Nelson, Shelley B;Kuhlbrodt, Kirsten;Hennings, J Christopher;Ericson, Johan;Sander, Maike
通讯作者：
Sander, Maike

Transgenic overexpression of the transcription factor Nkx6.1 in ýý-cells of mice does not increase ýý-cell proliferation, ýý-cell mass, or improve glucose clearance.

小鼠 γ-细胞中转录因子 Nkx6.1 的转基因过度表达不会增加 γ-细胞增殖、γ-细胞质量或改善葡萄糖清除率。

DOI：
发表时间：
2011-11
期刊：
影响因子：
0
作者：
Schaffer, Ashleigh E;Yang, Almira J;Thorel, Fabrizio;Herrera, Pedro L;Sander, Maike
通讯作者：
Sander, Maike

Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ α-cells.

胰岛自主胰岛素和平滑介导的信号调节胰高血糖素 α 细胞的身份变化。

DOI：
发表时间：
2018
期刊：
影响因子：
21.3
作者：
Cigliola, Valentina;Ghila, Luiza;Thorel, Fabrizio;van Gurp, Léon;Baronnier, Delphine;Oropeza, Daniel;Gupta, Simone;Miyatsuka, Takeshi;Kaneto, Hideaki;Magnuson, Mark A;Osipovich, Anna B;Sander, Maike;Wright, Christopher E V;Thomas, Melissa K
通讯作者：
Thomas, Melissa K

Immunohistochemical detection of beta-galactosidase or green fluorescent protein on tissue sections.

组织切片上β-半乳糖苷酶或绿色荧光蛋白的免疫组织化学检测。

DOI：
发表时间：
2007
期刊：
影响因子：
0
作者：
Seymour, Philip A;Sander, Maike
通讯作者：
Sander, Maike

Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function.

Neurog3 在表达激素的胰岛细胞中持续表达是内分泌成熟和功能所必需的。

DOI：
发表时间：
2009-06-16
期刊：
影响因子：
11.1
作者：
Wang, Sui;Jensen, Jan N;Seymour, Philip A;Hsu, Wei;Dor, Yuval;Sander, Maike;Magnuson, Mark A;Serup, Palle;Gu, Guoqiang
通讯作者：
Gu, Guoqiang