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Fox01 in Beta-Cell Compensation

Fox01 的 Beta 细胞补偿

基本信息

批准号：
8791685
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 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791685
关键词：
Address Adult Apoptosis Beta Cell Cell Differentiation process Cell Proliferation Cell Survival Cell physiology Cells Cellular Stress Chronic Coupling Cre-LoxP Cues Data Diabetes Mellitus Diet Embryo Embryonic Development Failure Fatty acid glycerol esters Financial compensation Functional disorder Gene Expression Gene Silencing Gene Targeting Gene Transfer Genetic Glucose Glucose Intolerance Goals Health Human Insulin Insulin Resistance Insulin-Like Growth Factor I Islet Cell Link Mediating Metabolism Molecular Target Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Oxidative Stress Pathogenesis Pathway interactions Physiological Play Production Rattus Refractory Risk Role Secondary to Signal Transduction Small Interfering RNA Stimulus Streptozocin System 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 knockout gene loss of function nutrition related genetics oxidation promoter 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(申请人提供)：β细胞代偿是一种适应性机制，通过这种机制，细胞增加胰岛素分泌，以克服胰岛素抵抗或氧化应激，从而维持肥胖患者的正常血糖。β细胞代偿最终导致细胞团的扩张和/或胰岛素合成/分泌的上调。细胞不能补偿胰岛素抵抗或氧化应激导致胰岛素不足和显性糖尿病。多么细胞补偿胰岛素抵抗或氧化应激，而导致细胞衰竭的原因却知之甚少。Foxo1是一种转录因子，它将胰岛素(或IGF-1)信号整合到细胞生存、增殖、分化、代谢和抗氧化的靶基因中。具有FoxO1基因变异的人类与细胞功能障碍和2型糖尿病的风险增加有关。我们发现，在胰岛中使用RIP(大鼠胰岛素启动子)诱导产生FoxO1的转基因小鼠可以预防脂肪诱导的葡萄糖耐量异常和链脲佐菌素诱导的糖尿病。这种效应归因于葡萄糖刺激的胰岛素分泌增加和RIP-FoxO1转基因小鼠细胞质量的增加。Foxo1活性在胰岛中上调，与饮食肥胖小鼠细胞代偿的生理诱导相关。这些新数据强调了FoxO1在细胞功能中的重要性，刺激了FoxO1有助于细胞代偿的假设。为了解决这一假设，我们提出了三个具体目标：1)确定FoxO1功能增强对胰岛素抵抗细胞补偿的影响；2)研究FoxO1增强细胞氧化应激补偿的机制；3)确定FoxO1功能丧失对肥胖和糖尿病细胞补偿的影响。为了实现这些目标，我们将使用基因转移、转基因表达、基因敲除和siRNA介导的基因沉默方法来实现细胞特异性FoxO1的产生，并在体内和体外的人胰岛中选择性地条件地去除FoxO1，然后确定具有FoxO1得失功能的细胞补偿胰岛素抵抗和氧化应激的能力。我们已经提供了原则性证明，并论证了该建议的可行性。完成这个项目将加深我们对糖尿病细胞代偿和细胞衰竭机制的理解。