Mechanisms of Glucose Toxicity

描述（由申请人提供）：糖尿病是心血管疾病、终末期肾病、失明和衰弱性神经病的主要原因。高血糖是这些疾病的根本原因，但葡萄糖毒性的机制尚不清楚。高血糖和氧化应激显著增加了0-连接的N-乙酰葡糖胺（0-GlcNAc）对蛋白质的酶促修饰，这是己糖胺生物合成途径的终点。0-GlcNAc是一种动态调节修饰，其类似于所有多细胞生物体和感染它们的病毒中的蛋白质磷酸化，并且与蛋白质磷酸化一样丰富。OGlcNAc和磷酸化之间的动态串扰作为营养/应激传感器来调节信号传导、转录和细胞骨架组装。血液中营养物质的增加，包括氨基酸、脂肪酸和葡萄糖，都会增加细胞蛋白质的GlcNAc酰化。越来越多的证据表明，升高的GlcNAc酰化是胰岛素抵抗和葡萄糖毒性的基础。 我们组建了一支由基础科学家和临床研究人员组成的多学科团队，他们是糖尿病心肌病、糖尿病视网膜病变、糖尿病神经病变和高血糖诱导的β细胞破坏方面的专家，以阐明葡萄糖毒性的常见基本机制。我们的假设是，营养素诱导的高GlcNAc酰化是葡萄糖毒性的基本机制，影响许多不同的细胞过程，包括通过电子传递链组分的异常GlcNAc酰化增加线粒体产生活性氧，蛋白激酶C和其他激酶的失调，改变转录因子（例如，转录因子）的活性和特异性。SP1），并通过影响多元醇的功能。通过组建一个由临床医生和生物化学家组成的团队，在与人类疾病最相关的不同模型系统和患者样本中研究葡萄糖毒性，我们不仅将揭示常见的疾病机制，还将了解葡萄糖毒性如何差异化地影响个体组织。这些研究将为糖尿病并发症的治疗和预防开辟新的途径。 公共卫生相关性：糖尿病是西方世界最流行的疾病之一。糖尿病的发病率和死亡率主要是由于葡萄糖毒性。然而，关于为什么过量的葡萄糖对组织有毒的分子机制知之甚少。我们已经组建了一个由医学专家和生物化学家组成的团队，以揭示葡萄糖毒性在疾病中最受影响的组织中的机制。所获得的数据将有助于开发新的预防和/或治疗方法。

DESCRIPTION (provided by applicant): Diabetes is a leading cause of cardiovascular disease, end-stage renal disease, blindness and debilitating neuropathies. Hyperglycemia is the root cause of these maladies, but the mechanisms of glucose toxicity are unclear. Hyperglycemia and oxidative stress dramatically increase the enzymatic modification of proteins by 0-linked N-acetylgiucosamine (0-GlcNAc), an endpoint of the hexosamine biosynthetic pathway. 0-GlcNAc is a dynamic regulatory modification that is both analogous to, and is as abundant as protein phosphorylation in all multi-cellular organisms and viruses that infect them. Dynamic crosstalk between OGlcNAc and phosphorylation serves as a nutrient/stress sensor to regulate signaling, transcription and cytoskeletal assembly. Increased nutrients in the blood, including amino acids, fatty acids and glucose, all increase GlcNAcylation of cellular proteins. Mounting evidence indicates that elevated GlcNAcylation underlies both insulin-resistance and glucose toxicity. We have assembled a multi-disciplinary team comprised of basic scientists and clinical investigators who are experts in diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy and hyperglycemia-induced beta-cell destruction, to elucidate the common fundamental mechanisms underlying glucose toxicity. It is our hypothesis that nutrient-induced hyper-GlcNAcylation is a fundamental mechanism of glucose toxicity, affecting many different cellular processes, including increasing the generation of reactive oxygen by the mitochondria via abnormal GlcNAcylation of electron transport chain components, dysregulation of protein kinase C and other kinases, altering the activity and specificity of transcription factors (eg. SP1), and via affecting functions ofpolyols. By assembling a team of clinicians and biochemists to study glucose toxicity in different model systems that are most relevant to human disease, and in patient samples, we will not only uncover common disease mechanisms, but also will learn how glucose toxicity differentially affects individual tissues. These studies will lead to novel avenues of treatment and prevention of diabetic complications. PUBLIC HEALTH RELEVANCE: Diabetes is amongst the most prevalent diseases in the Western world. The morbidity and mortality of diabetes is largely due to glucose toxicity. Yet, little is known about the molecular mechanisms as to why excessive glucose is toxic to tissues. We have assembled a team of both medical experts and biochemists to uncover the mechanisms of glucose toxicity in tissues most affected in the disease. The data obtained will allow the development of new preventions and/or treatments.