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（T2D）是一种多器官损害、衰弱和致命的流行病。根据美国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期，2360万人患有糖尿病。美国成年男性和成年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，患糖尿病儿童的人数也在上升。因此，T2D对人类健康构成严重威胁，并对卫生保健系统造成日益加重的负担。目前的治疗方法还远远不够理想。他们控制血糖，但不能解决原因，不能阻止疾病。我们希望将肌肉作为T2D基因治疗的平台，因为肌肉是人体最大的器官，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传递载体，以肌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T2D/肥胖小鼠（db/db）为动物模型，验证骨骼肌可以作为T2D基因治疗有效平台的假设。我们将系统地评估和改进治疗效果和安全性。我们还将研究证实临床结果的潜在分子机制。这项建议的成功将导致一种新的、有效的、安全的治疗T2D的方法。

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..