Myc Physiology in the Pancreatic Beta Cell

胰腺 Beta 细胞中的 Myc 生理学

基本信息

批准号：
10224945
负责人：
Adolfo Garcia-Ocana
金额：
$ 50.25万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-28 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224945
关键词：
1 year old Address Age Aging Apoptosis Apoptosis Inhibitor B Cell Proliferation Beta Cell Binding Binding Sites Bioenergetics Caloric Restriction Cell Cycle Cell Death Cell physiology Cells Cessation of life Data Development Diabetes Mellitus Diet Disease Epigenetic Process FRAP1 gene Failure Functional disorder Glucose Homeostasis Human Impairment Insulin Insulin Resistance Knowledge Lead MYC Family Protein Mediating Metabolic Metabolic stress Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Nutrient Overnutrition Pathway interactions Patients Phenocopy Physiological Physiology Play Process Protein Phosphatase 2A Regulatory Subunit PR53 Proto-Oncogene Proteins c-myc Publications Publishing Regulation Resistance Risk Rodent Role Structure of beta Cell of islet System Testing Therapeutic Toxic effect Up-Regulation aged cell growth demethylation design diabetes mellitus therapy feeding in vivo insight insulin secretion insulinoma islet novel therapeutic intervention overexpression recruit response transcription factor treatment strategy

项目摘要

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.

糖尿病患者将受益于增加功能性β细胞质量的疗法。 β细胞通过扩展其功能质量自然适应了代谢需求和胰岛素抵抗的增加，该过程随着衰老而降低。最近，我们在年轻小鼠但不是老鼠的功能β细胞的适应性扩张中表现出了至关重要的作用。尽管多项研究描述了MYC过表达在β细胞中的作用，但关于营养素如何调节β细胞中MYC表达的知识差异？ MYC如何参与β细胞中GSI和线粒体功能的调节，MYC如何增加衰老的β细胞的适应性增殖，或者靶向特定MYC结合位点的脱甲基增加β细胞增生的β细胞增殖在分泌压力的年龄β-Cells中？需要回答有关MYC在β细胞中的身体作用的这些重要问题，以促进我们的知识并找到治疗糖尿病的治疗方法。我们的总体假设是，MYC对于自适应β细胞的生长和功能至关重要，并且在T2D-易发或代谢压力的年龄β细胞中逆转MYC的抗性可能会导致增强的适应性反应。我们将通过完成以下特定目的来检验我们的假设：1）阐明营养在β细胞中的物理上调MYC以及是否需要MYC上调自适应葡萄糖和β细胞稳态中的胰岛素耐药性； 2）确定MYC在β细胞中胰岛素分泌和线粒体生物能的物理作用； 3）发现和修改了在代谢压力，年龄和T2Dβ细胞中损害MYC作用的机制。这些研究将提供前所未有的洞察力，了解MYC如何受到营养的调节，如何调节β细胞功能以及如何克服代谢应激的年龄型β细胞中的MYC耐药性，这将为设计和测试糖尿病治疗的新型治疗策略提供至关重要的基本平台。