CHLOROQUINE AND THE METABOLIC SYNDROME

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。氯喹已经使用多年，已经被证明可以降低糖尿病患者的血糖，降低胆固醇，可能还可以降低血压。虽然氯喹已经得到了广泛的研究，但其作用机制仍然不清楚。根据目前未发表的小鼠实验，已经确定了氯喹的一种新的潜在机制。此机制与自动柜员机相关。有令人信服的证据表明，ATM杂合子状态会在小鼠中产生代谢综合征。氯喹可以激活ATM，降低小鼠的血压、血糖和动脉粥样硬化(未发表的数据)。这一数据表明，ATM在调节人类代谢综合征方面发挥了积极作用。为了评估这一点，我们将招募25名年龄在18-55岁之间、符合代谢综合征标准的志愿者。实验将在三个肢体上进行，受试者作为自己的对照组：1)安慰剂3周，2)低剂量氯喹3周(根据性别，每天80-90毫克)，3)氯喹250 mg/天，3周。每个肢体都将接受口服葡萄糖耐量测试、胰岛素钳夹、动态血压监测和各种动脉粥样硬化标记物的实验室测试。单核细胞将被收集用于体外研究ATM活性的标记物。我们的目标是证明，氯喹，通过ATM作用，代表了一种新的潜在的代谢综合征治疗途径。提供这一概念证明将允许开发以ATM通路为靶点的新药物，并最终降低血管风险。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chloroquine has been used for many years and has been shown to decrease blood sugar in diabetics, lower cholesterol and possibly lower blood pressure. Although chloroquine has been extensivley studied, its mechanisms of action are still vague. A novel potential mechanism for chloroquine has been identified based on currently unpublished work in mice. This mechanism relates to ATM. There is compelling evidence evidece that the ATM heterozygous state produces the metabolic syndrome in mice. Chloroquine, which activates ATM, decreases blood pressure, blood glucose, and atherosclerosis in mice (unpublished data). This data suggests that ATM plays an active role in mediating the metabolic syndrome in humans. To assess this we will enroll 25 volunteers ages 18-55 that meet the criteria of the metabolic syndrome. The experiment will be conducted in 3 limbs, with subjects acting as their own controls: 1) Placebo for 3 weeks, 2) Low dose chloroquine for 3 weeks (80 to 90 mg/day based on gender), 3) Chloroquine 250 mg/day for three weeks. Each limb will be followed by an oral glucose tolerance test, insulin clamp, ambulatory blood pressure monitoring, and various lab tests for atherosclerosis markers. Monocytes will be collected for in vitro work on markers of ATM activity. Our goal is to prove that chloroquine, acting through ATM, represents a novel potential treatment pathway for the metabolic syndrome. Providing this proof of concept will allow the development of new agents that target the ATM pathway and ultimately decrease vascular risk.