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

• 批准号: 10266843
• 负责人: STEVEN ZHENG
• 金额: $ 38.27万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266843
• 关键词: Adult; American; Amino Acids; Anabolism; Animals; B Cell Proliferation; Basic Amino Acids; Beta Cell; Binding; Cell Line; Cell Maintenance; Cell model; Cell physiology; Cells; Cellular Metabolic Process; Chemicals; Diabetes Mellitus; Dietary Fats; Dietary Intervention; Disease; Exhibits; FRAP1 gene; Genetic Screening; Genetic Transcription; Genetically Engineered Mouse; Glucose Intolerance; Golgi Apparatus; Growth; Health; Histologic; Human; Hyperglycemia; Impairment; In Vitro; Insulin; Islets of Langerhans; Knock-out; Knowledge; Lead; Life; Lysosomes; Maintenance; Malignant Neoplasms; Mammals; Mediator of activation protein; Metabolic; Metabolism; Molecular; Monomeric GTP-Binding Proteins; Mus; Nutrient; Pathologic; Phosphorylation; Physiological; Physiological Processes; Play; Prediabetes syndrome; Prevention; Preventive; Publishing; Role; Signal Pathway; Signal Transduction; Source; Structure of beta Cell of islet; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Vacuole; Yeasts; base; 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

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（AAS）是生命的基本基础和燃料。它们也越来越被视为调节生长和代谢过程的化学信号。积累的证据清楚地表明，AA感应和信号在健康和疾病中起着至关重要的作用。 MTOR是AA灵敏度和信号传导的主调节器。最近的进步导致对AA如何激活MTOR的基本了解。 RAG是一种在溶酶体上发射的异二聚体小GTPase，被证明可激活MTOR，以响应AA刺激。令人惊讶的是，我们和其他人发现AA仍然可以激活抹布酵母和小鼠中的MTOR，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查，并鉴定出Rab1a是一种位于ER/Golgi上的小型GTPase，代表了MTOR上游的AA信号在酵母和哺乳动物中的AA信号传导的新颖的介体（Thomas等人，Thomas等人，癌细胞26：754）。迄今为止，尚不清楚AA-RAB1A信号的物理功能。因此，我们在年轻小鼠中产生了他莫昔芬引起的全身Rab1a敲除。 Rab1a基因敲除动物相对正常，除了暴露的高血糖和葡萄糖intlerance。进一步的分析表明，突变动物的β细胞质量明显较小，它们的β细胞经过了向α细胞的反差异。此外，在Rab1a敲除胰腺β细胞中，胰岛素mRNA和蛋白表达均显着降低。一致地，我们进一步表明AA-RAB1A信号传导调节β细胞系中的胰岛素转录。基于这些初步结果，我们建议测试以下假设：β细胞自主的AA-RAB1A信号传导通过控制胰岛素转录，β细胞增殖和哺乳动物的维持来控制葡萄糖稳态。我们将使用细胞和基因工程小鼠模型在正常生理和病理条件下剖析基本机制和意义。如果成功，该项目将增强有关营养如何控制全身葡萄糖稳态的基本知识。这也可能为糖尿病，癌症和其他相关疾病的营养和/或治疗性干预带来新的机会。