Fox01 in Beta-Cell Compensation

Fox01 的 Beta 细胞补偿

基本信息

批准号：
9187796
负责人：
HENGJIANG HENRY DONG
金额：
$ 33.89万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2018-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187796
关键词：
Address Adult Apoptosis Beta Cell Cell Differentiation process Cell Survival Cell physiology Cells Cellular Stress Chronic Coupling Cues Data Diabetes Mellitus Diet Embryo Embryonic Development FOXO1A gene Failure Fatty acid glycerol esters Financial compensation Functional disorder Gene Expression Gene Silencing Gene Targeting Gene Transfer Genetic Glucose Glucose Intolerance Goals High Fat Diet Human Impairment Insulin Insulin Resistance Insulin-Like Growth Factor I Islet Cell Knockout Mice Link Mediating Metabolism Molecular Target Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Nutritional Obese Mice Obesity Oxidative Stress Pathogenesis Pathologic Pathway interactions Physiological Play Production Rattus Refractory Risk Role SOD2 gene Secondary to Signal Transduction Small Interfering RNA Stimulus Streptozocin Tamoxifen Transgenic Mice Transgenic Organisms Up-Regulation Variant catalase feeding forkhead protein gain of function glutathione peroxidase in vivo insight insulin secretion insulin signaling islet knock-down knockout gene loss of function oxidation promoter public health relevance recombinase-mediated cassette exchange response tool transcription factor vector

项目摘要

DESCRIPTION (provided by applicant): Beta-cell compensation is an adaptive mechanism by which �-cells increase insulin secretion to overcome insulin resistance or oxidative stress for maintaining euglycemia in obesity. Beta-cell compensation culminates in the expansion of �-cell mass and/or upregulation of insulin synthesis/secretion. Failure of �- cells to compensate for insulin resistance or oxidative stress contributes to insulin insufficiency and overt diabetes. How �-cells compensate for insulin resistance or oxidative stress and what causes �-cell failure are poorly understood. FoxO1 is a transcription factor that integrates insulin (or IGF-1) signaling to target genes in cell survival, proliferation, differentiation, metabolism and anti-oxidation. Human with genetic FoxO1 variants are associated with an increased risk of �-cell dysfunction and type 2 diabetes. We show that transgenic mice with RIP (rat insulin promoter)-directed FoxO1 production in islets are protected against fat-induced glucose intolerance and streptozotocin-elicited diabetes. This effect is attributable to augmented glucose-stimulated insulin secretion and increased �-cell mass in RIP-FoxO1 transgenic mice. FoxO1 activity is upregulated in islets, correlating with the physiological induction of �-cell compensation in dietary obese mice. These new data underscore the importance of FoxO1 in �-cell function, spurring the hypothesis that FoxO1 contributes to �-cell compensation. To address this hypothesis, we propose three specific aims: 1) To determine the effect of FoxO1 gain-of-function on �-cell compensation for insulin resistance; 2) To address the mechanisms by which FoxO1 enhances �-cell compensation for oxidative stress; and 3) To determine the effect of FoxO1 loss-of-function on �-cell compensation in obesity and diabetes. To achieve these goals, we will employ gene transfer, transgenic expression, gene knockout and siRNA-mediated gene-silencing approaches to achieve �-cell specific FoxO1 production and alternatively conditional FoxO1 depletion in mature islets in vivo as well as in human islets ex vivo, followed by determining the ability of �-cells with FoxO1 gain- vs. loss-of-function to compensate for insulin resistance and oxidative stress. We have provided proof-of-principle and demonstrated the feasibility for the proposal. Accomplishing this project will deepen our understanding of the mechanisms of �-cell compensation and �- cell failure in diabetes.

描述（适用提供）：β细胞补偿是一种自适应机制，``细胞增加胰岛素分泌物以克服胰岛素抵抗或氧化应激，以维持肥胖症中的尤利西亚。 Beta细胞补偿最终导致 - 细胞质量的扩展和/或胰岛素合成/分泌的上调。细胞无法补偿胰岛素抵抗或氧化应激导致胰岛素不足和明显的糖尿病。如何 �细胞补偿胰岛素抵抗或氧化应激以及导致损坏的原因知之甚少。 FOXO1是一种转录因子，它将胰岛素（或IGF-1）信号整合到细胞存活，增殖，分化，代谢和抗氧化中的靶基因。具有遗传FOXO1变异的人与细胞功能障碍和2型糖尿病的风险增加有关。我们表明，具有RIP（大鼠胰岛素启动子）在胰岛中导向FOXO1产生的转基因小鼠受到保护，以防止脂肪诱导的葡萄糖intlerance和链蛋白酶诱发的糖尿病。这种作用归因于增强的葡萄糖刺激的胰岛素分泌和RIP-FOXO1转基因小鼠的细胞质量增加。 FOXO1活性在胰岛中进行了更新，与饮食肥胖小鼠的细胞补偿的物理诱导相关。这些新数据强调了FOXO1在``细胞函数''中的重要性，这刺激了FOXO1有助于``细胞补偿''的假设。为了解决这一假设，我们提出了三个具体目的：1）确定FOXO1功能获得对胰岛素抵抗的细胞补偿的影响； 2）解决FOXO1增强氧化应激补偿的机制； 3）确定FOXO1功能丧失对肥胖和糖尿病中细胞补偿的影响。为了实现这些目标，我们将采用基因转移，转基因表达，基因敲除和siRNA介导的基因分解方法，以实现特定的FOXO1产生以及在体内成熟胰岛中的FOXO1生产以及有条件的FOXO1在体内以及在人类胰岛中的成熟胰岛部署，然后在体内确定氧气损失的能力，以赔偿Foxo损失的能力。压力。我们提供了原则证明，并证明了该提案的可行性。完成该项目将加深我们对糖尿病中``细胞补偿''机制的理解。