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: 9754127
• 负责人: Erika Danielle Dean
• 金额: $ 14.53万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754127
• 关键词: Affect; Affinity; Alpha Cell; Amino Acid Transporter; Amino Acids; Arginine; Biochemical; Biological Assay; Biology; Blood; Blood Circulation; Catabolism; Cell Proliferation; Cell physiology; Cells; Cellular biology; Clinical Treatment; Clinical Trials; Complement; Data; Diabetes Mellitus; Disease; Environment; Enzymes; Event; Exercise; FRAP1 gene; Fasting; Fishes; Fractionation; Functional disorder; Funding; Gap Junctions; Gene Expression Profiling; Glucagon; Glucagon Receptor; Glucose; Glutamine; Goals; Grant; Hepatic; Hepatocyte; Homeostasis; Hormone secretion; Human; Hyperglycemia; Hyperplasia; Hypoglycemia; Image; Imaging Techniques; Impairment; Individual; Insulin-Dependent Diabetes Mellitus; Interruption; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Knock-out; Life; Liver; Manuscripts; Measures; Mentors; Mentorship; Metabolism; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Pathway interactions; Patients; Phase; Physicians; Proliferating; Proteomics; Publishing; Regulation; Research; Research Personnel; Research Training; Rodent; Scientist; Series; Serum; Signal Transduction; Talents; Testing; Therapeutic Intervention; Training; Transgenic Mice; Translations; Transplantation; Validation; Viral; Zebrafish; blood glucose regulation; career; detection of nutrient; ex vivo imaging; experience; hepatic gluconeogenesis; hyperglucagonemia; improved; in vitro Assay; in vivo; insight; interdisciplinary approach; islet; man; metabolomics; mouse model; multimodality; overexpression; programs; receptor function; response; selective expression; sensor; skills; skills training; small molecule; species difference; transcriptomics

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 高血糖导致2型糖尿病(T2D)的高血糖。因此，敌视 胰高血糖素作为T2D的一种治疗干预具有很大的前景。然而，高血糖素被打断 多种途径的信号转导导致α细胞的增殖和增殖。使用多学科 我们最近发现的一种方法，当肝脏中的胰高血糖素信号中断时，血液的积累 氨基酸(高氨基酸血症或AAHi)，特别是谷氨酰胺和精氨酸，推动α细胞的增殖。这些 研究还揭示了以前未被认识和保守的(鱼对人)肝-胰岛α细胞轴，其中 肝高血糖素信号调节血清氨基酸水平和AA增加，尤其是谷氨酰胺(Q)， 调节胰高血糖素的分泌和α-细胞的增殖和质量。AAHi是引起细胞的充要条件 以mTORC1依赖的方式增殖。我们假设AAHi在α中起作用。 细胞因为高表达一组独特的AA转运蛋白和催化酶，导致 MTORC 1激活、胰升糖素分泌和α-细胞增殖。我将采取一种实验性的策略， 利用鼠标模型在并行时识别路径和定义机制的优势 测试将我的发现转化为原始人类胰岛的方法。另外，我将利用一种新的体外检测胰岛α的方法- 人胰岛移植小鼠体内细胞增殖补充研究。这些研究将 扩大我们对控制α的分子机制的理解--细胞的生物学、功能、增殖和 并提供对胰岛细胞团可控和安全扩增途径的洞察。这些研究 也应该为T2D的正常α细胞功能以及α细胞功能障碍如何发生提供新的见解 减刑。