Myc Physiology in the Pancreatic Beta Cell

糖尿病患者将受益于增加功能性β细胞质量的治疗。β-细胞通过扩大其功能质量来自然地适应增加的代谢需求和胰岛素抵抗，这一过程随着年龄的增长而减少。我们最近展示了Myc在幼鼠而不是老年小鼠的功能性β细胞适应性扩增中的关键作用。尽管有多项研究描述了Myc在β细胞中过表达的影响，但对于这种关键的合成代谢转录因子如何感知和响应营养物质和增加的胰岛素需求，在其天然背景下仍存在知识空白。营养物质如何调节β-细胞中MYC的表达？Myc如何参与β细胞中Gsi和线粒体功能的调节，Myc如何未能促进老年β细胞的适应性增殖，或者特定Myc结合位点的靶向去甲基化是否会促进代谢应激老年β细胞的β细胞增殖？这些关于Myc在β细胞中的生理作用的重要问题需要得到回答，以促进我们的知识，并找到治疗糖尿病的方法。我们的主要假设是，Myc对适应性β细胞的生长和功能至关重要，逆转T2D倾向或代谢应激老化的β细胞的Myc抵抗可以导致增强的适应性反应。我们将通过完成以下具体目标来验证我们的假设：1)阐明营养物质如何在生理上上调β细胞中的Myc，以及在胰岛素抵抗中，Myc上调是否是适应性葡萄糖和β细胞稳态所必需的；2)确定Myc对β细胞中胰岛素分泌和线粒体生物能量学的生理作用；以及3)揭示和修改代谢应激、衰老和T2Dβ细胞中Myc作用的损害机制。这些研究将提供对Myc如何受营养物质调控、Myc如何调控β细胞功能以及如何克服代谢应激老化的β细胞中Myc抵抗的前所未有的见解，这将为设计和测试治疗糖尿病的新治疗策略提供重要的基础平台。

Patients with diabetes would benefit from therapies that increase functional β-cell mass. β-cells naturally adapt to increased metabolic demand and insulin resistance by expanding their functional mass, a process that decreases with aging. We have recently demonstrated a critical role for Myc in adaptive expansion of functional β-cells in young but not old mice. Despite multiple studies describing the effect of Myc overexpression in beta cells, there is a knowledge gap about how this crucial anabolic transcription factor perceives and responds to nutrients and increased insulin demand in its native context. How do nutrients regulate Myc expression in β-cells? How does Myc participate in the regulation of GSIS and mitochondrial function in the β-cell, how does Myc fail to increase adaptive proliferation in aged β-cells or will targeted demethylation of specific Myc binding sites increase β-cell proliferation in metabolically-stressed aged β-cells? These important questions about the physiological role of Myc in the β-cell need to be answered to advance our knowledge and find therapeutic means to treat diabetes. Our overarching hypothesis is that Myc is critical for adaptive β-cell growth and function, and reversing Myc resistance in the T2D-prone or metabolically-stressed aged β-cell can lead to an enhanced adaptive response. We will test our hypothesis by completing the following specific aims: 1) To elucidate how nutrients physiologically upregulate Myc in β-cells and whether Myc upregulation is required for adaptive glucose and β-cell homeostasis in insulin resistance; 2) To determine the physiological role of Myc on insulin secretion and mitochondrial bioenergetics in the β-cell; and, 3) To uncover and modify the mechanisms impairing Myc action in the metabolically-stressed, aged, and T2D β-cells. These studies will deliver unprecedented insight into how Myc is regulated by nutrients, how Myc regulates β-cell function and how to overcome Myc resistance in the metabolically-stressed aged β-cell, which will provide a crucial basic platform for designing and testing novel therapeutic strategies for the treatment of diabetes.