Muscle as a Platform for Type 2 Diabetes Treatment by Gene Delivery

肌肉作为基因传递治疗 2 型糖尿病的平台

• 批准号: 8105547
• 负责人: Xiao Xiao
• 金额: $ 37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105547
• 关键词: Activins; Address; Adipose tissue; Adult; Affect; American; Animal Model; Animals; Atrophic; Beta Cell; Blood; Blood Glucose; Body fat; Cardiac; Cell Survival; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Consumption; Data; Defect; Dependovirus; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Effectiveness; Epidemic; Fatty acid glycerol esters; Follistatin; Gene Delivery; Genes; Goals; Growth; Growth Factor; Health; Healthcare Systems; Heart; Human; Hyperglycemia; Inbred C57BL Mice; Insulin; Insulin Resistance; Insulin Signaling Pathway; Kidney; Lead; Leptin; Lipids; Longevity; Mediating; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Muscle; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Polymers; Polyuria; Prediabetes syndrome; Proteins; Role; Running; Safety; Serum; Signal Pathway; Site; Skeletal Muscle; Societies; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; Woman; adeno-associated viral vector; base; blood glucose regulation; cost; db/db mouse; diabetes mellitus therapy; disorder prevention; drug candidate; experience; gene therapy; glucose disposal; glucose tolerance; improved; insulin secretion; insulin sensitivity; islet; leptin receptor; lipid metabolism; men; metabolomics; mutant; myostatin; novel; reconstitution; research and development; research study; small molecule; statistics; success; theories; therapeutic gene; tool; vector; Activins; Address; Adipose tissue; Adult; Affect; American; Animal Model; Animals; Atrophic; Beta Cell; Blood; Blood Glucose; Body fat; Cardiac; Cell Survival; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Consumption; Data; Defect; Dependovirus; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Effectiveness; Epidemic; Fatty acid glycerol esters; Follistatin; Gene Delivery; Genes; Goals; Growth; Growth Factor; Health; Healthcare Systems; Heart; Human; Hyperglycemia; Inbred C57BL Mice; Insulin; Insulin Resistance; Insulin Signaling Pathway; Kidney; Lead; Leptin; Lipids; Longevity; Mediating; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Muscle; Myopathy; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Organ; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Polymers; Polyuria; Prediabetes syndrome; Proteins; Role; Running; Safety; Serum; Signal Pathway; Site; Skeletal Muscle; Societies; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Treatment Efficacy; Woman; adeno-associated viral vector; base; blood glucose regulation; cost; db/db mouse; diabetes mellitus therapy; disorder prevention; drug candidate; experience; gene therapy; glucose disposal; glucose tolerance; improved; insulin secretion; insulin sensitivity; islet; leptin receptor; lipid metabolism; men; metabolomics; mutant; myostatin; novel; reconstitution; research and development; research study; small molecule; statistics; success; theories; therapeutic gene; tool; vector

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is a multi-organ damaging, debilitating and lethal disease on an epidemic scale. According to Center for Disease Control and Prevention, at least 54 million American adults had pre-diabetes and 23.6 million had diabetes. The obesity rates in the US have now reached 32.2% and 35.5% among adult men and women. Even more concerning, children with T2D are on the rise along with their rising obesity rates. Thus, T2D poses a grave threat to human health and an escalating burden to the health care system. Current therapies are far from ideal. They manage blood glucose but poorly address the causes and fail to stop the disease. We wish to use muscle as a platform for T2D gene therapy, since muscle is the largest organ in the body and a major site for insulin-mediated glucose homeostasis and energy consumption. Based on our encouraging preliminary studies, we will continue to use adeno-associated virus as the muscle gene delivery vector, myostatin propeptide and follistatin as the therapeutic genes, the commonly used leptin receptor defective T2D/obesity mice (db/db) as the animal model, to test our hypothesis that skeletal muscles can be an effective platform for T2D gene therapy. We will systematically evaluate and improve the therapeutic efficacies as well as safety profiles. We will also investigate potential molecular mechanisms that substantiate the clinical outcomes. The success of this proposal should lead to a new, effective and safe therapy for T2D. PUBLIC HEALTH RELEVANCE: Type-2 diabetes afflicts tens of millions Americans. The costs to the society and specifically to the health care system are enormous (greater than $174 billion in 2007 according to data from CDC). This RO1 proposal plans to develop a gene therapy approach using diabetic and obese mouse as a model. The success of this proposal will lead to new ways and new drug candidates for the treatment of type 2 diabetes..

描述（由申请人提供）：2型糖尿病（T2D）是一种流行病量表的多器官损害，衰弱和致命疾病。根据疾病控制与预防中心的数据，至少有5400万美国成年人患有糖尿病前，有2360万患有糖尿病。成年男女的肥胖率现在已经达到32.2％和35.5％。更令人担忧的是，T2D的儿童随着肥胖率的上升而上升。因此，T2D对人类健康构成了严重的威胁，并对医疗保健系统造成了不断升级的负担。当前的疗法远非理想。他们管理血糖，但无法解决原因，无法阻止疾病。我们希望将肌肉用作T2D基因疗法的平台，因为肌肉是体内最大的器官，也是胰岛素介导的葡萄糖稳态和能量消耗的主要部位。 Based on our encouraging preliminary studies, we will continue to use adeno-associated virus as the muscle gene delivery vector, myostatin propeptide and follistatin as the therapeutic genes, the commonly used leptin receptor defective T2D/obesity mice (db/db) as the animal model, to test our hypothesis that skeletal muscles can be an effective platform for T2D gene therapy.我们将系统地评估和提高治疗效率以及安全性。我们还将研究证实临床结果的潜在分子机制。该提案的成功应导致T2D的新，有效且安全的治疗。 公共卫生相关性：2型糖尿病会折磨数千万美国人。社会，特别是医疗保健系统的成本是巨大的（根据CDC的数据，2007年超过1740亿美元）。该RO1建议计划使用糖尿病和肥胖小鼠作为模型开发一种基因治疗方法。该提案的成功将导致新的方法和新药物治疗2型糖尿病。