Jagged 1-Notch signaling determines β cell maturity and function

锯齿状 1-Notch 信号传导决定 β 细胞成熟度和​​功能

• 批准号: 10315442
• 负责人: Nina Suda
• 金额: $ 7.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315442
• 关键词: Beta Cell; Binding; Blindness; Cardiovascular system; Cell physiology; Cells; Chronic; Clinical; Data; Defect; Development; Disease; Dominant-Negative Mutation; End stage renal failure; Endocrine; Epidemic; Failure; Family; Functional disorder; Genetic; Glucose; Glucose Intolerance; Goals; Health Care Costs; High Fat Diet; Human; Hyperglycemia; Immunofluorescence Immunologic; Impairment; In Vitro; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Ligands; Mammals; Measures; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pancreas; Pathogenicity; Pathway interactions; Patients; Peripheral; Pharmacology; Phenotype; Physiological; Prevalence; Publishing; Reagent; Recording of previous events; Research Personnel; Role; Signal Transduction; Surface; Testing; Therapeutic; Tissues; Toxic effect; Training; Translating; Visualization; Work; adenoviral-mediated; blood glucose regulation; db/db mouse; diabetes pathogenesis; feeding; gain of function; glucose tolerance; in vivo; insulin secretion; islet; jagged1 protein; leptin receptor; loss of function; mortality; mouse model; notch protein; novel; novel therapeutic intervention; prevent; receptor; response; skills; translational approach

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.

总结/摘要 肥胖引起的2型糖尿病（T2 DM）继续以惊人的速度增加，导致大量 长期并发症和医疗费用的负担。T2 DM现在是终末期肾病的主要原因 也是全球失明的主要原因之一，也是心血管疾病的不成比例的贡献者。 发病率和死亡率。因此，了解T2 DM发病机制是解决日益严重的 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，但它仅在糖尿病患者中表现为高血糖症。 β细胞功能不全。这种失败的病理生理机制需要进一步阐明。 我们最近已经表明，Notch信号传导是β细胞功能和葡萄糖稳态的新调节剂。凹口 活性受配体（锯齿状1/2和δ样1/3/4）可用性调节。我们发现从HFD喂养的胰岛中分离出来的胰岛 或瘦素受体缺陷型db/db小鼠与食物或db/+对照相比具有增加的Jagged 1表达， 而其他Notch配体没有变化，与Notch活性增加平行。这些数据让我们假设， Jagged 1是β细胞Notch信号转导的充分和必要条件，是β细胞Notch信号转导的潜在调节因子。 功能、成熟度和葡萄糖稳态（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 Jagged 1功能获得性和敲除小鼠。通过识别配体-受体相互作用，我们假设我们可以 利用这些知识来获得治疗益处。为此，我们培育了显性负突变体， Notch受体缺乏细胞内Notch结构域，可特异性阻断Jagged或Delta样配体。 作为一种转化方法，我们将研究是否在患有和不患有糖尿病的患者的胰岛中也观察到增加的Jagged 1。 T2 DM（目标3）。目前关于β细胞中Notch信号传导的数据显示了进一步理解Notch信号传导的希望。 T2 DM的病理生理学。在进一步研究这一机制时，我们希望提供一种新的治疗策略， 预防一种在全球范围内日益受到关注的疾病。 本培训计划将培养我在理解β细胞功能和成熟度的决定因素方面的技能， 设置高血糖。研究Jagged 1-Notch信号传导的拟议研究将是实现 我的目标是成为一名独立的研究人员。