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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

基本信息

批准号：
8826733
负责人：
Xiao Xiao
金额：
$ 32.93万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8826733
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

项目摘要

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.

描述（由申请人提供）：2 型糖尿病 (T2D) 是一种流行性的多器官损伤、衰弱和致命疾病。根据疾病控制和预防中心的数据，至少 5400 万美国成年人患有糖尿病前期，2360 万成年人患有糖尿病。美国成年男性和女性的肥胖率目前分别达到32.2%和35.5%。更令人担忧的是，患有 T2D 的儿童数量随着肥胖率的上升而增加。因此，T2D 对人类健康构成严重威胁，并给医疗保健系统带来不断加重的负担。目前的治疗方法远非理想。他们控制血糖，但未能很好地解决病因，也未能阻止疾病的发生。我们希望利用肌肉作为 T2D 基因治疗的平台，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场所。基于我们令人鼓舞的初步研究，我们将继续使用腺相关病毒作为肌肉基因传递载体，肌生长抑制素前肽和卵泡抑素作为治疗基因，常用的瘦素受体缺陷型T2D/肥胖小鼠（db/db）作为动物模型，来检验我们的假设，即骨骼肌可以作为T2D基因治疗的有效平台。我们将系统地评估和提高治疗效果和安全性。我们还将研究证实临床结果的潜在分子机制。该提案的成功应该会带来一种新的、有效且安全的 T2D 治疗方法。