Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration

α细胞增生和β细胞再生中的肝胰岛和胰岛内串扰

基本信息

批准号：
10540191
负责人：
WILLIAM L HOLLAND
金额：
$ 45.48万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540191
关键词：
Ablation Aftercare Alpha Cell Amino Acids Animal Model Apoptosis Apoptotic Area B-Lymphocytes Beta Cell Blood Glucose CHES1 gene Carbohydrates Cell Survival Cells Communication Data Diabetic mouse Dissection Ductal Epithelial Cell FGF2 gene Fasting Fatty acid glycerol esters Fc Receptor Fibroblast Growth Factor Receptors Functional Regeneration Genetic Genetic Transcription Glucagon Glucagon Receptor Gluconeogenesis Glucose Hepatic Hormones Human Hyperplasia Impairment Inbred NOD Mice Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Link Liver Mediating Mediator of activation protein Metabolic Diseases Modeling Monoclonal Antibodies Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Panic Persons Pharmaceutical Preparations Phosphorylation Plasma Prevention Production Proteins Publishing Recombinant Fibroblast Growth Factor Rodent Role Signal Transduction Skeletal Muscle Source Structure of alpha Cell of islet Tetracyclines Tissues Transcription Repressor Transgenic Mice Up-Regulation Work amino acid metabolism antagonist blood glucose regulation cell regeneration diabetic euglycemia functional restoration glucose production improved in vivo in vivo regeneration incretin hormone insulin secretion islet mouse model non-diabetic novel overexpression pancreatic juice precursor cell prevent promoter regenerative uptake

项目摘要

ABSTRACT While evaluating the potential for glucagon receptor antagonists (GRAs) to maintain glucose homeostasis in T1D rodents, we noted that GRAs promote β−cell survival and regeneration. Remarkably, GRA-treated mice maintained normal blood glucose, even after the treatment was withdrawn. Our recently published data suggest that: 1) ablation or antagonism of the glucagon receptor (GcgR) blunts apoptosis and stimulates regeneration of functional β-cell mass in mice; 2) much of this new insulin+ mass derives from the conversion of α−cell precursors into insulin-producing cells; and 3) GRAs restore sustainable euglycemia and insulin production in diabetic NOD mice and in mice grafted with human islets. Our preliminary results suggest that the β-cytotrophic effects of GRAs occur through both islet autonomous effects and through a well described liver- α-cell axis4-7 which triggers α-cell hyperplasia through AA-dependent mechanisms (Figure 1). We have identified Foxn3, a glucagon-responsive transcriptional repressor and novel mediator of glycemia8-11, as the previously-undefined integrator by which glucagon alters amino acid metabolism. In parallel, we have identified the GRA-driven upregulation of fibroblast growth factor 2 (FGF2), a target of the proliferative transcriptional co-factor Yes-associated protein 1 (YAP1) that is expressed in Sox9+ ductal cells, as a key contributor to GRA-mediated revival of a regenerative niche within the islet. We hypothesize that impaired glucagon action promotes hepatic Foxn3-mediated α-cell hyperplasia via changes in amino acid metabolism and an FGF2-mediated regenerative niche within the islet to allow α-cell to β-cell conversion in T1D. We will evaluate our hypothesis using a cadre of novel, validated, and uniquely-suited mouse models which facilitate our genetic dissection of the mechanisms linking the loss of glucagon signaling to altered hepatic utilization of amino acids, α-cell hyperplasia, and the restoration of functional β-cell mass via two aims. 1) Using PANIC- ATTAC diabetic mice, cultured murine islets, and cultured human islets, we will examine the islet-autonomous effects of glucagon receptor antagonism or ablation on β-cell survival and β-cell regeneration. 2) We will examine α-cell hyperplasia, β-cell survival and the regeneration of functional β−cell mass after liver-specific deletion or overexpression of Foxn3.

抽象的在评估胰高血糖素受体拮抗剂（GRA）维持葡萄糖稳态的潜力时在 T1D 啮齿类动物中，我们注意到 GRA 可以促进 β 细胞存活和再生，值得注意的是，GRA 治疗的小鼠。正常血糖，甚至在停止治疗后仍维持正常。表明：1) 胰高血糖素受体 (GcgR) 的消融或拮抗会减弱细胞凋亡并刺激小鼠功能性 β 细胞质量的再生；2) 这种新的胰岛素+质量大部分来自转化 α 细胞前体转化为胰岛素产生细胞；3) GRA 恢复可持续的正常血糖和胰岛素我们的初步结果表明，糖尿病 NOD 小鼠和移植人类胰岛的小鼠中的产量。 GRA 的 β 细胞营养作用通过胰岛自主效应和充分描述的肝脏作用发生。 α 细胞 axis4-7 通过 AA 依赖性机制触发 α 细胞增生（图 1）。鉴定出 Foxn3，一种胰高血糖素反应性转录阻遏蛋白和新型血糖介质 8-11，以前未定义的胰高血糖素改变氨基酸代谢的积分器同时，我们有。确定了 GRA 驱动的成纤维细胞生长因子 2 (FGF2) 的上调，FGF2 是增殖的靶标转录辅因子 Yes 相关蛋白 1 (YAP1) 在 Sox9+ 导管细胞中表达，作为关键有助于 GRA 介导的胰岛内再生生态位的复兴。胰高血糖素作用通过改变氨基酸代谢促进肝脏 Foxn3 介导的 α 细胞增生胰岛内的 FGF2 介导的再生生态位允许 T1D 中的 α 细胞向 β 细胞转化。使用一系列新颖、经过验证且独特的小鼠模型来评估我们的假设，这些模型有助于我们对胰高血糖素信号传导丧失与肝脏利用之间的机制进行了基因剖析氨基酸、α 细胞增生和功能性 β 细胞质量的恢复有两个目的 1) 使用 PANIC-。 ATTAC 糖尿病小鼠、培养的小鼠胰岛和培养的人类胰岛，我们将检查胰岛自主性胰高血糖素受体拮抗或消融对 β 细胞存活和 β 细胞再生的影响 2) 我们将。检查肝脏特异性治疗后 α 细胞增生、β 细胞存活和功能性 β 细胞团的再生 Foxn3 的缺失或过度表达。