Amino acid regulation of pancreatic islet alpha cell proliferation and function

氨基酸调节胰岛α细胞增殖和功能

• 批准号: 10394072
• 负责人: Erika Danielle Dean
• 金额: $ 7.26万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394072
• 关键词: Alpha Cell; Amino Acids; Arginine; Biology; Blood; Cell Proliferation; Cell physiology; Cells; Cellular biology; Complement; Disease; Enzymes; Fishes; Functional disorder; Funding; Gap Junctions; Glucagon; Glutamine; Goals; Hepatic; Human; Hyperglycemia; Hyperplasia; Interruption; Islet Cell; Islets of Langerhans; Liver; Mentors; Mentorship; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Phase; Regulation; Research; Research Personnel; Scientist; Serum; Signal Transduction; Talents; Testing; Therapeutic Intervention; Training; Translations; Transplantation; career; hyperglucagonemia; in vitro Assay; in vivo; insight; interdisciplinary approach; islet; man; mouse model; programs; skills

Project Summary Hyperglucagonemia contributes to the hyperglycemia of type 2 diabetes (T2D). As such, antagonism of glucagon action has great promise as a therapeutic intervention for T2D. However, interrupted glucagon signaling by multiple approaches leads to α-cell proliferation and hyperplasia. Using a multidisciplinary approach we recently discovered when glucagon signaling is interrupted in the liver, the accumulation of blood amino acids (hyperaminoacidemia or AAHi), particularly glutamine and arginine, drive α-cell proliferation. These studies also revealed a previously unappreciated and conserved (fish to man) hepatic-islet α-cell axis where hepatic glucagon signaling regulates serum amino acid levels and increased AA, especially glutamine (Q), regulate glucagon secretion and α-cell proliferation and mass. AAHi is necessary and sufficient to cause -cell proliferation in an mTORC1-dependent manner. We hypothesize that AAHi exerts the effect specifically in α- cells because of the high expression of a unique set of AA transporters and catalytic enzymes, leading to mTORC1 activation, glucagon secretion and α-cell proliferation. I will pursue an experimental strategy that leverages the advantages of mouse models for identifying pathways and defining mechanisms while in parallel testing the translation my findings into primary human islets. Plus, I will utilize a new in vitro assay for islet α- cell proliferation to complement in vivo studies in mouse with transplanted human islets. These studies will expand our understanding of the molecular mechanisms controlling α-cell biology, function, proliferation, and mass and provide insight into pathways for controlled and safe expansion of islet cell mass. These studies should also provide new insights into normal α-cell function and how the α-cell dysfunction in T2D could be mitigated.

项目摘要 高葡萄糖血症有助于2型糖尿病（T2D）的高血糖。因此，对抗的 胰高血糖作用是对T2D的治疗干预措施的巨大希望。但是，胰高血糖素中断 通过多种方法的信号导致α细胞增殖和增生。使用多学科 方法我们最近发现何时在肝脏中中断glocagon信号传导时，血液的积累 氨基酸（高氨基酸血症或AAHI），尤其是谷氨酰胺和精氨酸，驱动α细胞增殖。这些 研究还揭示了先前没有批准的且构成（人与人）肝α细胞轴，其中 肝谷氨酰胺信号传导调节血清氨基酸水平并增加AA，尤其是谷氨酰胺（Q），， 调节胰高血糖素的分泌和α细胞增殖和质量。 AAHI是必要的，足以引起细胞 以MTORC1依赖性方式增殖。我们假设AAHI在α-中专门执行了有效 细胞由于一组独特的AA转运蛋白和催化酶的表达高，导致 MTORC1激活，胰高血糖素分泌和α细胞增殖。我将采取一种实验策略 利用鼠标模型的优势来识别途径和定义机制，同时并行 测试我的发现为主要人类小岛的翻译。另外，我将利用一种新的体外测定胰岛α- 通过移植的人类胰岛在小鼠中进行体内研究的细胞增殖。这些研究会 扩展我们对控制α细胞生物学，功能，增殖和的分子机制的理解 质量并提供有关控制胰岛细胞质量的控制和安全扩展的途径的洞察力。这些研究 还应提供有关正常α细胞功能以及T2D中α细胞功能障碍的新见解 缓解。