Molecular mechanisms underlying reduction of alcohol consumption by PPAR agonists

PPAR 激动剂减少饮酒的分子机制

• 批准号: 9171918
• 负责人: Laura Brockway Ferguson
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171918
• 关键词: Affect; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alzheimer' s Disease; Amygdaloid structure; Area; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Biochemical; Brain; Characteristics; Clinical Trials; Complex; Crime; Data; Dependovirus; Development; Drug Targeting; Dyslipidemias; Environment; FDA approved; Fenofibrate; Gene Expression; Genes; Goals; Health; Health Care Costs; Hormone Receptor; Huntington Disease; Hyperlipidemia; Immunohistochemistry; In Vitro; Investigation; Knock-out; Knockout Mice; Knowledge; Ligands; Link; Liver Failure; Maintenance; Measures; Mediating; Mental disorders; Messenger RNA; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurosciences; Neurosciences Research; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Hormone Receptors; Nucleus Accumbens; Obesity; PPAR alpha; Parkinson Disease; Pathway interactions; Peripheral; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Predisposition; Prefrontal Cortex; Productivity; Property; Proteins; Quality of life; Quantitative Reverse Transcriptase PCR; Relapse; Research; Rodent; Safety; Schizophrenia; Severities; Societies; Stress; Techniques; Testing; Therapeutic; Therapeutic Intervention; Ventral Tegmental Area; Viral; Withdrawal; Work; addiction; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol response; alcohol use disorder; alcoholism therapy; cell type; efficacy trial; experience; improved; in vivo; individual patient; insight; knock-down; male; novel; problem drinker; public health relevance; receptor; small hairpin RNA; smoking addiction; transcription factor; treatment response

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.

描述（由申请人提供）：酗酒影响数百万人，并给社会带来高昂的医疗费用、工作效率下降和犯罪率上升的负担。由于目前批准的三种治疗方法效果有限，因此迫切需要改进治疗方法。过氧化物酶体增殖物激活受体 (PPAR) 是核激素受体，充当配体激活转录因子。最近的证据表明，PPAR 激动剂具有抗成瘾特性，并为治疗酗酒者提供了未经探索的治疗干预措施。 PPAR 激动剂在治疗酗酒方面具有独特的有前景的药理潜力，因为它们已被证明可以缓解酗酒者面临的四种主要疾病：酗酒、肝功能衰竭、神经退行性疾病和吸烟成瘾。拟议的研究将调查 PPAR 激动剂抗成瘾特性的机制。第一个目标将使用免疫组织化学和 qRT-PCR 来确定成瘾神经回路区域中 PPAR 同种型的基线分布和定位。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 PPAR 在体内对于减少 PPAR 激动剂治疗后饮酒行为的重要性。 这项研究将为相对较新且未经探索的成瘾研究领域提供重要的新知识。通过了解 PPAR 激动剂如何促进减少饮酒，该项目的结果将揭示有趣的新药理学靶点，并促进发现可能有助于酒精中毒的起始、维持或进展的新基因和途径。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，可以解决复杂行为与治疗或病症引起的潜在分子变化之间的差异。拟议的研究将产生在分子水平上将 PPAR 通路与酒精相关行为联系起来的关键证据，并且是重新定位 PPAR 激动剂作为酒精中毒治疗方法的重要一步。本研究中正在研究的 PPAR 激动剂已表现出相当良好的安全性，并且已获得 FDA 批准用于治疗血脂异常，因此无需经过漫长的安全性和有效性试验即可迅速成为酒精中毒的新治疗方法。此外，这项研究的结果可能会扩展到其他成瘾和精神疾病，在这些疾病中，PPAR 激动剂已显示出治疗潜力，从而提高帕金森病、阿尔茨海默病和亨廷顿病等许多疾病患者的生活质量。