Effects of ACE2 gene therapy on Diabetes

ACE2基因治疗对糖尿病的影响

基本信息

批准号：
8102099
负责人：
ERIC D LAZARTIGUES
金额：
$ 16.82万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8102099
关键词：
ACE2 enzyme Address Adenoviruses Adipose tissue Affect Age American Angiotensin II Angiotensin II Receptor Angiotensin II Signaling Pathway Angiotensin-Converting Enzyme Inhibitors Angiotensins Animal Model Beta Cell Binding Sites Blood Glucose Blood flow Carboxypeptidase Cardiovascular Diseases Cardiovascular system Catabolism Cell physiology Cells Cleaved cell Clinical Clinical Trials Code Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Disease Elements Enzymes Epidemic Functional disorder Gender Gene Expression Goals Homologous Gene Hyperactive behavior Hyperglycemia In Vitro Indium Insulin Insulin Resistance Islets of Langerhans Kidney Knock-out Knockout Mice Link Liver Mediating Messenger RNA Methodology Modeling Molecular Mono-S NADPH Oxidase Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Oxidative Stress Pancreas Peptides Peptidyl-Dipeptidase A Peripheral Phase Physiological Play Predisposing Factor Production Proteins Public Health Reactive Oxygen Species Regulation Renin-Angiotensin System Reporting Risk Risk Factors Role Signal Transduction Structure of beta Cell of islet Testing Tissues Virus Western World angiotensin I (1-7)blood glucose regulation blood perfusion clinically relevant db/db mouse diabetic gene therapy glycemic control improved in vivo insulin secretion islet leptin receptor mouse model novel prevent promoter public health relevance receptor tool transcription factor type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): Diabetes is a growing problem in all parts of the World. Clinical trials and animal models of type I and type II diabetes have shown that hyperactivity of angiotensin-II (Ang-II) signaling pathways contribute to the development of diabetes and diabetic complications. Of clinical relevance, blockade of the renin-angiotensin system (RAS) prevents new-onset diabetes and reduces the risk of diabetic complications. Angiotensin converting enzyme (ACE) 2 is a recently discovered mono- carboxypeptidase and the first homolog of ACE. It is thought to inhibit Ang-II signaling cascades mostly by cleaving Ang-II to generate Ang-(1-7), which effects oppose Ang-II and are mediated by the Mas receptor. The enzyme is present in various tissues and organs, including the kidney, liver, adipose tissue and pancreas. Its expression is elevated in the endocrine pancreas in diabetes and in the early phase during diabetic nephropathy. Pancreatic islets express both RAS components and NADPH oxidase (Nox) components, which are key elements in mediating oxidative stress. In the islet Ang-II and oxidative stress are both capable of decreasing insulin gene expression and secretion. ACE2 is hypothesized to oppose the ACE/Ang-II/AT1 receptor axis and may protect pancreatic beta- cell function by inhibiting both Nox activity and the Ang-II-mediated reduction of insulin gene expression and secretion. To manipulate ACE2 expression, we generated a novel adenovirus coding for ACE2 and reported increased ACE2 mRNA, protein and activity in cells and tissues. We hypothesize that ACE2 over-expression in the pancreas will reduce oxidative stress and ameliorate beta-cell function, thus leading to improved glucose homeostasis in diabetic mice. To test this hypothesis, we will address the following specific aims: 1) Determine the existence of a relationship between ACE2 expression and/or activity and diabetes; 2) Evaluate the consequences of ACE2 over-expression in diabetic mice; 3) Establish whether ACE2 over-expression improves pancreatic beta-cell function in diabetes. To achieve these goals, we will first use ACE2 knockout and db/db mouse (type 2 diabetes) models to establish the relationship between ACE2 and diabetes. Then we will combine state of the art molecular, pharmacological and physiological tools for in vitro (isolated islets) and in vivo (pancreas) gene therapy in pre-diabetic and young diabetic db/db mice. Finally, we will address the mechanisms by which ACE2 could potentially counterbalance the deleterious effects of the hyperactive RAS in diabetes. This proposal will show evidence of the beneficial effects of ACE2 over-expression on the normalization of blood glucose and highlight ACE2 as a new target for the treatment of diabetes. PUBLIC HEALTH RELEVANCE: Approximately 8% of Americans are affected by diabetes, a well known risk factor for cardiovascular diseases, and it is expected to grow due to the current obesity epidemic in the Western World. Using gene therapy in a mouse model of type 2 diabetes, this application will describe the ability of a new enzyme, ACE2, to regulate blood glucose levels. If confirmed, ACE2 could become a new target for the treatment of type 2 diabetes.

描述（由申请人提供）：糖尿病在世界各地都是一个日益严重的问题。 I 型和 II 型糖尿病的临床试验和动物模型表明，血管紧张素-II (Ang-II) 信号通路的过度活跃有助于糖尿病和糖尿病并发症的发生。具有临床意义的是，阻断肾素-血管紧张素系统（RAS）可预防新发糖尿病并降低糖尿病并发症的风险。血管紧张素转换酶 (ACE) 2 是最近发现的一种单羧肽酶，也是 ACE 的第一个同系物。人们认为它主要通过裂解 Ang-II 生成 Ang-(1-7) 来抑制 Ang-II 信号级联反应，Ang-(1-7) 的作用是对抗 Ang-II 并由 Mas 受体介导。该酶存在于多种组织和器官中，包括肾、肝、脂肪组织和胰腺。其表达在糖尿病患者的内分泌胰腺中以及糖尿病肾病的早期阶段升高。胰岛表达 RAS 成分和 NADPH 氧化酶 (Nox) 成分，它们是介导氧化应激的关键元素。在胰岛中，Ang-II 和氧化应激都能够降低胰岛素基因的表达和分泌。据推测，ACE2 与 ACE/Ang-II/AT1 受体轴相反，并可能通过抑制 Nox 活性和 Ang-II 介导的胰岛素基因表达和分泌减少来保护胰腺 β 细胞功能。为了操纵 ACE2 表达，我们生成了一种编码 ACE2 的新型腺病毒，并报告了细胞和组织中 ACE2 mRNA、蛋白质和活性的增加。我们假设胰腺中 ACE2 的过度表达将减少氧化应激并改善 β 细胞功能，从而改善糖尿病小鼠的葡萄糖稳态。为了检验这一假设，我们将实现以下具体目标：1）确定 ACE2 表达和/或活性与糖尿病之间是否存在关系； 2）评估糖尿病小鼠中ACE2过度表达的后果； 3) 确定 ACE2 过度表达是否可以改善糖尿病患者的胰腺 β 细胞功能。为了实现这些目标，我们将首先使用ACE2敲除和db/db小鼠（2型糖尿病）模型来建立ACE2与糖尿病之间的关系。然后，我们将结合最先进的分子、药理学和生理学工具，对糖尿病前期和年轻糖尿病 db/db 小鼠进行体外（分离胰岛）和体内（胰腺）基因治疗。最后，我们将探讨 ACE2 可能抵消糖尿病中过度活跃的 RAS 的有害影响的机制。该提案将证明 ACE2 过度表达对血糖正常化的有益影响，并强调 ACE2 作为糖尿病治疗的新靶点。公共卫生相关性：大约 8% 的美国人受到糖尿病的影响，糖尿病是众所周知的心血管疾病危险因素，并且由于西方世界目前肥胖流行，预计这一数字还会增加。在 2 型糖尿病小鼠模型中使用基因疗法，该应用将描述一种新酶 ACE2 调节血糖水平的能力。如果得到证实，ACE2可能成为治疗2型糖尿病的新靶点。