权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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（由申请人提供）：β细胞补偿是一种适应性机制，β细胞通过这种机制增加胰岛素分泌，以克服胰岛素抵抗或氧化应激，从而维持肥胖症的正常状态。β-细胞补偿最终导致β-细胞质量的扩大和/或胰岛素合成/分泌的上调。β细胞不能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 β-细胞补偿胰岛素抵抗或氧化应激，而导致β-细胞衰竭的原因却知之甚少。FoxO 1是一种转录因子，它整合胰岛素（或IGF-1）信号传导到细胞存活、增殖、分化、代谢和抗氧化的靶基因。具有遗传FoxO 1变异的人与β细胞功能障碍和2型糖尿病的风险增加有关。我们发现，RIP（大鼠胰岛素启动子）指导FoxO 1在胰岛生产的转基因小鼠对脂肪诱导的葡萄糖耐受不良和链脲佐菌素引起的糖尿病。这种效应可归因于RIP-FoxO 1转基因小鼠中葡萄糖刺激的胰岛素分泌增加和β细胞质量增加。FoxO 1活性在胰岛中上调，与饮食性肥胖小鼠中β细胞补偿的生理诱导相关。这些新的数据强调了FoxO 1在β细胞功能中的重要性，激发了FoxO 1有助于β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标：1）确定FoxO 1功能获得对β细胞补偿胰岛素抵抗的影响; 2）解决FoxO 1增强β细胞补偿氧化应激的机制; 3）确定FoxO 1功能丧失对肥胖和糖尿病β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介导的基因沉默方法来实现β细胞特异性FoxO 1的产生，以及体内成熟胰岛和离体人类胰岛中的条件性FoxO 1消耗，然后确定具有FoxO 1获得与功能丧失的β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证明，并证明了该提案的可行性。完成这个项目将加深我们对糖尿病中β细胞代偿和β细胞衰竭机制的理解。