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

描述（由申请人提供）：2型糖尿病（T2 D）是一种流行规模的多器官损伤、衰弱和致死性疾病。根据疾病控制和预防中心的数据，至少有5400万美国成年人患有糖尿病前期，2360万人患有糖尿病。美国成年男性和女性的肥胖率分别达到32.2%和35.5%。更令人担忧的是，随着肥胖率的上升，患有T2 D的儿童也在沿着上升。因此，T2 D对人类健康构成严重威胁，并给医疗保健系统带来不断增加的负担。目前的治疗方法远非理想。他们控制血糖，但不能很好地解决原因，也不能阻止疾病。我们希望使用肌肉作为T2 D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部位。基于我们令人鼓舞的前期研究，我们将继续以腺相关病毒为肌肉基因载体，以肌肉生长抑制素前肽和卵泡抑素为治疗基因，以常用的瘦素受体缺陷型T2 D/肥胖小鼠（db/db）为动物模型，验证骨骼肌可以作为T2 D基因治疗的有效平台的假设。我们将系统地评估和改善治疗效果以及安全性。我们还将研究证实临床结果的潜在分子机制。该提案的成功将为T2 D提供一种新的，有效的和安全的治疗方法。 公共卫生相关性：2型糖尿病困扰着数千万美国人。对社会，特别是对卫生保健系统的成本是巨大的（根据疾病预防控制中心的数据，2007年超过1740亿美元）。该RO 1提案计划使用糖尿病和肥胖小鼠作为模型开发基因治疗方法。该提案的成功将为2型糖尿病的治疗带来新的方法和新的候选药物。

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..