An in vivo screening system for chemical modulators of eating behavior

项目摘要 我们的申请题为“一种用于进食行为化学调节剂的体内筛选系统”， 写信回应资助机会PA-16-374，题为：“检测开发和筛选发现 NIDDK感兴趣的疾病的治疗或成像剂”。此次融资机会旨在为 发展表型分析，以无偏筛选调节疾病的分子 相关终点。PA-16-374特别包括使用模式生物（例如C. elegans）that can 概括与健康有关的结果的重要方面。 过度的体重增加是抗精神病药物的常见副作用，并增加了 2型糖尿病和代谢综合征的发展。代谢副作用的普遍存在 抗精神病药物的高不依从率，这是治疗的一个主要挑战。 心理健康食物摄入量增加（摄食过多）在驱动抗精神病药物诱导的体重方面起着重要作用 但超噬作用的机制尚不清楚。利用我们最近开发的 基于微量滴定法的C.我们发现抗精神病药物，如氯氮平和奥氮平， 也能诱导C.优雅我们的基因分析显示基础食物摄入量和抗精神病药物 诱导的摄食过多在遗传上是不同的，并且有可能抑制抗精神病药物的副作用 而不影响基础食物摄入量。拟议的筛选将确定潜在的辅助治疗， 抑制抗精神病药引起食欲亢进。筛选1，549种FDA批准的药物，优化药理学 动力学和安全性，而不是具有未知责任的化合物，提供了最快的测试途径 临床上潜在的辅助治疗。作为概念验证，我们对197名FDA 已批准的药物在C.并确定米诺环素抑制抗精神病药诱导的摄食过多， 蠕虫重要的是，我们的后续研究表明，米诺环素治疗还抑制了食欲过盛， 小鼠体重增加，并逆转奥氮平诱导的下丘脑基因表达的变化。功率 使用数百万年进化分离的模式物种，进一步增加了 潜在佐剂对人类受试者的作用的可转化性。我们的方法提供了一个快速和有效的 确定可以快速转移到临床的潜在辅助治疗的途径，因此与 公共卫生随着全球肥胖和糖尿病发病率的增长，减轻体重的重要性 抗精神病药物的效果变得更加重要。这些研究也与 NIDDK的使命是预防或改善治疗后出现的副作用并阐明其机制 精神药物通过这些途径产生不良代谢事件。

Project Summary Our application entitled ”An in vivo screening system for chemical modulators of eating behavior” has been written to respond to funding opportunity PA-16-374 entitled: “Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of Interest to the NIDDK”. This funding opportunity seeks to fund the development of phenotypic assays that allow for unbiased screens for molecules that modulate disease relevant endpoints. PA-16-374 specifically includes the use of model organisms (e.g. C. elegans) that can recapitulate important aspects of health-related outcomes. Excessive body weight gain is a common side effect of antipsychotic drugs and increases the risk for development of type 2 diabetes and metabolic syndrome. The prevalence of metabolic side effects contributes to the high rate of non-compliance with antipsychotic medication, which is a major challenge in the treatment of mental health. Increased food intake (hyperphagia) plays a large role in driving antipsychotic-induced weight gain but the mechanisms underlying the hyperphagic effect are unknown. Using our recently developed microtiter based food intake assay in C. elegans we find that antipsychotics such as clozapine and olanzapine also induce hyperphagia in C. elegans. Our genetic analysis revealed that basal food intake and antipsychotic induced hyperphagia are genetically distinct and that it is possible to suppress the antipsychotic side effect without affecting basal food intake. The proposed screen will identify potential adjuvant treatments that can suppress antipsychotic-induced hyperphagia. Screening 1,549 FDA approved drugs with optimized pharmaco- kinetics and safety, rather than compounds with unknown liabilities, provides the fastest route to testing potential adjuvant therapies in the clinic. As a proof of concept we conducted a small pilot screen of 197 FDA approved drugs in C. elegans and identified that minocycline suppressed antipsychotic-induced hyperphagia in worms. Importantly, our follow up studies show that minocycline treatment also suppresses hyperphagia and weight gain in mice and reverses changes in hypothalamic gene expression induced by olanzapine. The power of using model species separated by millions of years of evolution, further increase the potential for translatability of effects of potential adjuvants to human subjects. Our approach provides a fast and efficient route to identify potential adjuvant therapies that can be moved quickly to the clinic and is thus relevant to public health. As the global incidence of obesity and diabetes grows, the importance of mitigating the weight gain effects of antipsychotics becomes even more important. These studies are also highly relevant to the NIDDKs mission to prevent or ameliorate treatment-emergent side effects and delineate the mechanisms through which psychotropic medications produce adverse metabolic events.