Molecular mechanisms underlying reduction of alcohol consumption by PPAR agonists

 描述(申请人提供)：酗酒影响数百万人，并给社会带来高昂的医疗成本、工作效率损失和犯罪率上升的负担。目前迫切需要改进治疗方法，因为目前批准的三种治疗方法只有一定的效果。过氧化物酶体增殖物激活受体(PPAR)是作为配体激活的转录因子的核激素受体。最近的证据表明，PPAR激动剂具有抗成瘾特性，为治疗酒精依赖者提供了尚未探索的治疗干预措施。PPAR激动剂具有治疗酒精中毒的独特前景的药理学潜力，因为它们已被证明可以缓解酗酒者面临的四大疾病：酗酒、肝功能衰竭、神经退行性变和吸烟成瘾。这项拟议的研究将探讨PPAR激动剂的抗成瘾特性的机制。第一个目标将使用免疫组织化学和qRT-PCR来确定PPAR亚型在成瘾神经回路区域的基线分布和定位。第二个和第三个目标将使用病毒介导的基因操作和小鼠行为模型来测试体内PPAR对于减少酒精消费行为的重要性，以回应PPAR激动剂的治疗。这项研究将为一个相对较新和未被探索的成瘾研究领域提供至关重要的新知识。通过了解PPAR激动剂如何促进减少酒精消耗，该项目的结果将涉及有趣的新的药理靶点，并有助于发现可能有助于酒精中毒的启动、维持或进展的新基因和新途径。通过将药物、基因和行为联系起来，这些数据可能具有更广泛的科学意义，因为它解决了复杂行为与治疗或疾病引起的潜在分子变化之间的差异。这项拟议的研究将产生在分子水平上将PPAR途径与酒精相关行为联系起来的关键证据，并是将PPAR激动剂重新定位为酒精中毒治疗的重要一步。这项研究中研究的PPAR激动剂已经显示出相当良好的安全性，并且已经被FDA批准用于治疗血脂异常，因此可能很快成为治疗酒精中毒的新疗法，而不需要进行漫长的安全性和有效性试验。此外，这项研究的结果可能扩展到PPAR激动剂已显示出治疗潜力的其他成瘾和精神障碍，从而提高许多疾病的个体患者的生活质量，如帕金森氏症、阿尔茨海默氏症和亨廷顿病。

 DESCRIPTION (provided by applicant): Alcoholism affects millions of people and burdens society with high healthcare costs, lost work productivity and increased crime rates. There is an urgent need for improved treatments since the three that are currently approved are only modestly effective. Peroxisome proliferator activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. Recent evidence suggests that PPAR agonists possess anti-addictive characteristics and offer unexplored therapeutic intervention for treating alcoholics. PPAR agonists possess a uniquely promising pharmacologic potential for treating alcoholism since they have been demonstrated to alleviate the top four ailments confronting alcoholics: alcohol abuse, liver failure, neurodegeneration and smoking addiction. The proposed research will investigate the mechanisms that impart the anti-addictive properties of PPAR agonists. The first aim will use immunohistochemistry and qRT- PCR to determine the baseline distribution and localization of PPAR isotypes in regions of addiction neurocircuitry. The second and third aims will use viral-mediated gene manipulation and mouse behavioral models to test the importance of PPARs in vivo for decreased alcohol consumption behavior in response to treatment with a PPAR agonist. This study will provide crucial new knowledge about a relatively new and unexplored area of addiction research. By understanding how PPAR agonists can facilitate decreased alcohol consumption, results from this project will implicate interesting new pharmacological targets and facilitate the discovery of novel genes and pathways that might contribute to the initiation, maintenance, or progression of alcoholism. By linking drug, genes, and behavior, this data may have a broader scientific significance by resolving the disparity between complex behaviors and underlying molecular changes induced by a treatment or condition. The proposed research will generate critical evidence linking the PPAR pathway on a molecular level to alcohol-related behavior, and is an important step towards repositioning PPAR agonists as treatment for alcoholism. The PPAR agonist under investigation in this study has demonstrated a reasonably favorable safety profile and is already FDA approved for dyslipidemia so could quickly become a new treatment for alcoholism without lengthy safety and efficacy trials. Furthermore, the results of this research may extend to other addictions and psychiatric disorders where PPAR agonists have demonstrated therapeutic potential, thereby increasing the quality of life for individual patients of many illnesses like Parkinson's, Alzheimer's and Huntington's disease.