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Sex dependent function of the orphan nuclear receptor Nr4a1 in the pancreatic beta cell during Type 2 Diabetes disease progression

2 型糖尿病疾病进展过程中胰腺 β 细胞中孤儿核受体 Nr4a1 的性别依赖性功能

基本信息

批准号：
10202936
负责人：
Jeffery Sivert Tessem
金额：
$ 44.12万
依托单位：
BRIGHAM YOUNG UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

项目摘要

A central aspect of type 2 diabetes disease progression is impaired functional beta cell mass. The hyperglycemic and hyperlipidemic environment present in type 2 diabetes corresponds with impaired beta cell function. The orphan nuclear receptor Nr4a1 is critical for fuel utilization in various tissues, however little is known regarding its function in the beta cell. Nr4a1 expression is decreased in the beta cell of rodent models of type 2 diabetes, as well as in primary human islets from type 2 diabetic patients. Our preliminary data demonstrate that beta cell specific Nr4a1 deletion in the context of high fat feeding results in impaired glucose tolerance in female mice. While there is a clear connection between Nr4a1 and type 2 diabetes disease progression in female mice, there is a fundamental gap in our understanding of Nr4a1 in the beta cell in terms of 1) the effect of estrogen signaling on Nr4a1 in female beta cells, 2) the transcriptional changes dependent on Nr4a1 loss in the context of high fat feeding that lead to glucose intolerance, and 3) how these observed phenotypes apply to beta cell function in gestational diabetes. These gaps hinder the rationale design of targeted therapies to improve functional beta cell mass as a treatment for type 2 diabetes in women. The long-term goal is to develop strategies to improve beta cell function, proliferation and survival to improve patient outcomes. The overall objective of this proposal is to determine the mechanism by which beta cell Nr4a1 loss results in high fat diet mediated impaired glucose tolerance in females. Our central hypothesis is that Nr4a1 is a key downstream target of estrogen signaling in the beta cell, and that Nr4a1 loss under high fat feeding predisposes the animal to beta cell failure and ultimately impaired glucose tolerance and diabetes. Guided by our preliminary data, this hypothesis will be tested in the following specific aims: Aim 1: Determine the effect of estrogen signaling on Nr4a1 expression in the beta cell. Aim 2: Determine the Nr4a1 mediated transcriptional changes in the beta cell that impair glucose tolerance in high fat fed females. Aim 3: Determine the effect of Nr4a1 beta cell deletion in a mouse model of gestational diabetes. The proposal is innovative because it elucidates novel functions of Nr4a1 regulation by estrogen in the female beta cell. The proposed research is significant because it fills fundamental gaps in our understanding of an understudied beta cell regulator, Nr4a1, its regulation by the estrogen signaling pathway, and the link to increased type 2 diabetes in postmenopausal women and gestational diabetes in pregnant women.

2型糖尿病疾病进展的一个中心方面是功能性β细胞群受损。 2型糖尿病患者的高血糖和高血脂环境对应于 β细胞功能受损孤儿核受体Nr4a1对核燃料利用至关重要，各种组织，然而关于其在β细胞中的功能知之甚少。Nr4a1表达在2型糖尿病的啮齿动物模型的β细胞中以及在原发性人类中，来自2型糖尿病患者的胰岛。我们的初步数据表明，β细胞特异性高脂喂养条件下Nr4a1基因缺失导致女性糖耐量异常小鼠虽然Nr4a1与2型糖尿病疾病进展之间存在明显联系，在雌性小鼠中，我们对β细胞中Nr4a1的理解存在根本性的差距，术语1）雌激素信号传导对雌性β细胞中Nr4a1的影响，2）转录水平的影响，在高脂喂养的情况下，依赖于Nr4a1损失的变化导致葡萄糖不耐受，以及3）这些观察到的表型如何适用于妊娠期β细胞功能糖尿病这些差距阻碍了靶向治疗的合理设计，以改善功能性 2型糖尿病的治疗方法有哪些？长期目标是发展改善β细胞功能、增殖和存活以改善患者预后的策略。本提案的总体目标是确定β细胞Nr4a1 损失导致高脂肪饮食介导的女性葡萄糖耐量受损。我们的中央假设Nr4a1是β细胞中雌激素信号传导的关键下游靶点，高脂肪喂养下的Nr4a1损失使动物易于β细胞衰竭，葡萄糖耐量受损和糖尿病。根据我们的初步数据，这一假设将是目的1：确定雌激素信号传导对Nr4a1的影响在beta细胞中的表达。目的2：确定Nr4a1介导的转录变化，在高脂肪喂养的雌性动物中损害葡萄糖耐量的β细胞。目标3：确定妊娠糖尿病小鼠模型中Nr4a1 β细胞缺失。该提案具有创新性因为它阐明了雌性β细胞中雌激素对Nr4a1调节的新功能。这项拟议中的研究意义重大，因为它填补了我们对一种未充分研究的β细胞调节因子Nr4a1，它通过雌激素信号通路进行调节，绝经后妇女2型糖尿病和妊娠期糖尿病增加的联系孕妇