Jagged 1-Notch signaling determines β cell maturity and function

摘要/摘要 肥胖诱发的2型糖尿病(T2 DM)继续以惊人的速度增加，导致 长期并发症和医疗费用的负担。2型糖尿病现在是终末期肾病的主要原因 是世界范围内导致失明的主要原因之一，也是心血管疾病的一个不成比例的因素 发病率和死亡率。因此，了解T2 DM的发病机制是解决日益增长的 一些人认为这是人类历史上最大的流行病。 虽然胰岛素抵抗是2型糖尿病(T2 DM)的标志，但只有在 β细胞不足的设置。导致这一失败的病理生理学机制需要进一步阐明。 我们最近发现Notch信号是β细胞功能和葡萄糖动态平衡的一种新的调节因子。凹槽 活性受配体(锯齿状1/2和类似Delta的1/3/4)可用性的调节。我们发现从以HFD为食的动物体内分离出的胰岛 或者瘦素受体缺陷的db/db小鼠与对照相比增加了Jagged1的表达， 在Notch活性增加的同时，其他Notch配体没有变化。这些数据使我们假设 Jagged1是β细胞Notch信号转导的充分必要条件，是β细胞的潜在调节因子 功能、成熟度和血糖稳态(目标1和目标2)。为了研究这一点，我们产生了新的β细胞特异性 Jagged1功能增强和基因敲除小鼠。通过识别配体-受体的相互作用，我们假设我们可以 充分利用这些知识，以获得治疗上的好处。为此，我们产生了显性负突变 Notch受体缺乏细胞内的Notch结构域，该结构域专门阻止锯齿状或Delta样配体。 作为一种翻译方法，我们将调查在患有和不患有胰岛疾病的患者中是否也发现Jagged1增加 T2 DM(目标3)。目前有关β细胞中Notch信号转导的数据为进一步了解 2型糖尿病的病理生理学研究在进一步研究这一机制的过程中，我们希望提供一种新的治疗策略。 预防这种疾病仍然是世界范围内日益关注的问题。 这项培训计划将发展我的技能，以了解β细胞功能和成熟度的决定因素 高血糖的设定。拟议中的研究锯齿状1-Notch信号将是迈向 我成为一名独立研究人员的目标。

Summary/Abstract Obesity-induced Type 2 Diabetes (T2DM) continues to increase at an alarming rate resulting in a substantial burden of long-term complications and healthcare costs. T2DM is now the leading cause of end-stage renal disease and one of the leading causes of blindness worldwide, as well as a disproportionate contributor to cardiovascular morbidity and mortality. As such, understanding mechanisms of T2DM pathogenesis is key in tackling the growing prevalence in what some consider the largest epidemic in human history. Although insulin resistance is the hallmark of Type 2 diabetes (T2DM), it manifests as hyperglycemia only in the setting of β cell insufficiency. Pathophysiologic mechanisms underlying this failure requires further elucidation. We have recently shown that Notch signaling is a novel regulator of β cell function, and glucose homeostasis. Notch activity is regulated by ligand (Jagged 1/2, and Delta-like 1/3/4) availability. We find that islets isolated from HFD-fed or leptin receptor-deficient db/db mice have increased Jagged1 expression as compared to chow or db/+ controls, without change in other Notch ligands, in parallel to increased Notch activity. These data led us to hypothesize that Jagged1 is both sufficient and necessary to transduce Notch signaling in β cells and is a potential regulator of β cell function, maturity and glucose homeostasis (Aim 1 and Aim 2). To investigate this, we generated novel β cell specific Jagged1 gain-of-function and knock-out mice. By identifying the ligand-receptor interaction, we postulate that we can take advantage of this knowledge for therapeutic benefit. To this end, we have generated dominant negative mutants of the Notch receptor lacking the intracellular Notch domain that specifically block either Jagged or Delta-like ligands. As a translational approach, we will investigate if increased Jagged1 is also seen in islets from patients with and without T2DM (Aim 3). The current data on Notch signaling in β cells shows promise for furthering the understanding of the pathophysiology in T2DM. In studying this mechanism further, we hope to provide a novel therapeutic strategy in preventing a disease that continues to be a growing concern worldwide. This training plan will develop my skills in understanding determinants of β cell function and maturity in the setting of hyperglycemia. The proposed study investigating Jagged 1-Notch signaling will be a stepping stone towards my goal of becoming an independent researcher.