Amino Acids-Rab1A Nutrient Signaling in the Regulation of Glucose Homeostasis

氨基酸-Rab1A 营养信号在血糖稳态调节中的作用

基本信息

批准号：
10684889
负责人：
STEVEN ZHENG
金额：
$ 38.27万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
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：
2020-09-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684889
关键词：
Adult Alpha Cell American Amino Acids Anabolism Animals Basic Amino Acids Beta Cell Binding Cell Line Cell Maintenance Cell Proliferation Cell model Cell physiology Cellular Metabolic Process Chemicals Diabetes Mellitus Dietary Fats Dietary Intervention Disease Exhibits FRAP1 gene Genetic Screening Genetic Transcription Genetically Engineered Mouse Glucose Glucose Intolerance Golgi Apparatus Growth Health Histologic Homeostasis Human Hyperglycemia Impairment In Vitro Insulin Islets of Langerhans Knock-out Knockout Mice Knowledge Life Lysosomes Maintenance Malignant Neoplasms Mammals Mediator Metabolic Metabolism Molecular Monomeric GTP-Binding Proteins Mus Nutrient Pathologic Phosphorylation Physiological Physiological Processes Play Prediabetes syndrome Prevention Preventive Proliferating Publishing Role Signal Pathway Signal Transduction Source Structure of beta Cell of islet Tamoxifen Testing Therapeutic Therapeutic Intervention Vacuole Yeasts blood glucose regulation cancer cell cell growth cell type cellular engineering detection of nutrient glucose metabolism glycemic control in vivo insight knockout animal mRNA Expression mouse model mutant novel promoter protein expression public health relevance response transcription factor transdifferentiation yeast genetics young adult

项目摘要

Amino acids (AAs) are basic building blocks and fuels of life. They are also increasingly appreciated as chemical signals that regulate growth and metabolic processes. Accumulating evidence clearly show that AA sensing and signaling play a critical role in health and diseases. mTOR is a master regulator of AA sensing and signaling. Recent progress has led to some basic understanding of how AA activates mTOR. Rag, a heterodimeric small GTPase anchored on the lysosomes, was shown to activate mTOR in response to AA stimulation. Surprisingly, we and others found that AAs can still activate mTOR in Rag-knockout yeast and mice, indicating that an alternative AA signaling mechanism exists. In a recently published study, we carried out a yeast genetic screening and identified Rab1A, a small GTPase localized on the ER/Golgi, represents a novel, conserved mediator of AA signaling upstream of mTOR in yeast and mammals (Thomas et al., Cancer Cell 26:754). To date, the physiological functions of AA-Rab1A signaling are not known. Therefore, we generated tamoxifen- induced whole body Rab1A knockout in young adult mice. Rab1A knockout animals were relatively normal except exhibiting hyperglycemia and glucose intolerance. Further analysis showed that the mutant animals had significantly smaller β-cell mass and their β-cells underwent trans-differentiation to α-cells. Moreover, both insulin mRNA and protein expression were markedly reduced in Rab1A knockout pancreatic β-cells. Consistently, we further showed that AA-Rab1A signaling regulated insulin transcription in β-cell lines. Based on these preliminary results, we propose to test the hypothesis that β-cell-autonomous AA-Rab1A signaling controls glucose homeostasis by regulating insulin transcription, β-cell proliferation and maintenance in mammals. We will dissect the basic mechanisms and significance under normal physiological and pathological conditions using cell and genetically engineered mouse models. If successful, this project will enhance the basic knowledge on how nutrients control whole body’s glucose homeostasis. It could also lead to new opportunities for nutritional and/or therapeutic intervention for diabetes, cancer and other related diseases.

氨基酸 (AA) 是生命的基本组成部分和燃料，越来越多的证据表明，AA 传感和信号传导在健康和疾病中发挥着关键作用。 Rag 是 AA 传感和信号转导的主要调节因子，最近的进展使我们对 AA 如何激活 mTOR 有了一些基本的了解。令人惊讶的是，我们和其他人发现，在 Rag 敲除酵母和小鼠中，AA 仍然可以激活 mTOR，这表明存在另一种 AA 信号机制。在最近发表的一项研究中，我们进行了酵母遗传筛选，并鉴定了 Rab1A（一种小型 GTP 酶）。 ER/高尔基体上的 AA 信号通路代表了酵母和哺乳动物中 mTOR 上游 AA 信号传导的一种新型保守介导物 (Thomas 等人，Cancer Cell 26:754)。 AA-Rab1A信号传导的生理功能尚不清楚，因此，我们在年轻成年小鼠中产生了他莫昔芬诱导的全身Rab1A敲除动物，除了表现出高血糖和葡萄糖不耐症外，突变动物的体形明显较小。此外，在 Rab1A 敲除的胰腺中，β 细胞团及其 β 细胞向 α 细胞转分化。一致地，我们进一步表明 AA-Rab1A 信号传导在 β 细胞系中调节胰岛素转录，基于这些初步结果，我们建议检验 β 细胞自主 AA-Rab1A 信号传导通过调节葡萄糖稳态的假设。我们将利用细胞和基因工程小鼠模型来剖析正常生理和病理条件下的胰岛素转录、β细胞增殖和维持的基本机制和意义。关于营养物质如何控制全身葡萄糖稳态的研究还可能为糖尿病、癌症和其他相关疾病的营养和/或治疗干预带来新的机会。