Preclinical neuroprotective trials of a PPAR-gamma agonist in HD mouse models

描述（由申请人提供）：亨廷顿病（HD）是一种神经退行性疾病，由亨廷顿基因CAG重复序列的病理性延长引起。没有治疗方法可以延缓人类发病和/或减缓疾病进展。转录失调和线粒体功能障碍与HD的发病机制密切相关。过氧化物酶体增殖物激活受体（PPARs）是配体激活转录因子核激素受体家族的成员。PPAR吗?激活防止神经元退化，同时增加线粒体活力。最近的研究也提供了证据，证明PPAR？在HD细胞模型中，激动剂具有神经保护作用并增加线粒体功能。我们的初步研究表明突变的亨廷顿蛋白改变了PPAR？细胞模型和小鼠模型中HD和PPAR？激动剂罗格列酮在细胞模型中保护细胞免受突变亨廷顿诱导的细胞死亡，并延长HD小鼠模型的存活时间。因此，我们建议确定PPAR的可能性。激活改善突变亨廷顿蛋白诱导的体内病理和功能障碍。在Aim 1中，我们将在片段突变型亨廷顿蛋白转基因小鼠模型（N171-82Q小鼠）中确定ppar - γ激动剂罗格列酮对疾病发生和进展的剂量反应和影响。我们将对N171-82Q HD小鼠长期给予三次剂量的罗格列酮（10、20、40 mg/kg/天，i.p）。在症状前试验中，药物注射将在6周龄开始，在症状试验中，药物注射将在12周龄开始。运动行为表现将由加速旋转棒仪评估。罗格列酮对脑萎缩的影响将在6、12和18周龄进行症状前试验，在16、20周龄进行症状性试验，通过结构MRI纵向检查。疾病的发病将通过第一次检测到的旋转体缺陷来评估。采用HPLC/MS/MS法测定药物浓度。罗格列酮对脑病理改变的影响也将通过组织学分析进行评估。在Aim 2中，我们将在全长突变亨廷顿蛋白转基因小鼠模型（BACHD小鼠）中确定罗格列酮对运动功能和脑病理的影响。我们将在发病前和发病后对BACHD小鼠长期给予最佳剂量的罗格列酮。运动行为表现将由旋转记录仪评估。在6个月和12个月时用MRI检查脑萎缩，12个月时用组织学检查神经病理。拟议的研究将为PPAR的进一步临床试验提供关键证据。人类的激动剂。我们的长期目标是为HD患者开发有效的治疗药物。

DESCRIPTION (provided by applicant): Huntington disease (HD) is a neurodegenerative disease that is caused by the pathological elongation of the CAG repeats in the huntingtin gene. There is no treatment to delay onset and/or slow down the progression of disease in humans. Transcriptional dysregulation and mitochondrial dysfunction have been strongly implicated in the pathogenesis of HD. Peroxisome proliferator- activated receptors (PPARs) are members of the nuclear hormone receptor family of ligand- activated transcription factors. PPAR? activation prevents neuronal degeneration with a concomitant increase in mitochondrial viability. Recent studies have also provided evidence that PPAR? agonists are neuroprotective and increase mitochondrial function in a cell model of HD. Our preliminary studies indicated that mutant huntingtin altered the PPAR? levels in both cell models and mouse model of HD, and PPAR? agonist rosiglitazone protected cells against mutant huntingtin-induced cell death in cell models and extended survival in a HD mouse model. Therefore, we propose to determine the possibility of PPAR? activation to ameliorate mutant huntingtin-induced pathology and dysfunction in vivo. In Aim 1, we will determine the dose response and effect of PPAR-gamma agonist rosiglitazone on disease onset and progression in a fragment mutant huntingtin transgenic mouse model (N171-82Q mice). We will chronically administer three doses of rosiglitazone (10, 20, 40 mg/kg/day, i.p) to N171-82Q HD mice. Drug injection will be started at 6 weeks of age for presymptomatic trials and at 12 weeks of age for symptomatic trials. Motor behavioral performance will be assessed by accelerating rotarod apparatus. Effect of rosiglitazone on brain atrophy will be examined longitudinally by using structural MRI at 6, 12 and 18 weeks of age for presymptomatic trials and at 16, 20 weeks for symptomatic trials. The onset of disease will be evaluated by first detectable rotarod deficit. Drug concentrations will be measured by HPLC/MS/MS. Effect of rosiglitazone on brain pathological change will be also evaluated by histological analysis. In Aim 2, we will determine the effect of rosiglitazone on motor function and brain pathology in a full-length mutant huntingtin transgenic mouse model (BACHD mice). We will chronically administer optimal dose of rosiglitazone to BACHD mice before onset and after onset of motor deficit. Motor behavioral performance will be assessed by rotarod apparatus. Brain atrophy will be examined by using MRI at 6 and 12 months of age and neuropathology will be examined by histology at 12 months. The proposed study will provide critical evidence for further clinical trials of PPAR? agonists in humans. Our long-term goal is to develop effective therapeutic agents for HD patients. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is the most common inherited disorder affecting the nervous system in humans and shares many features with other neurodegenerative diseases. There is no cure, nor are there effective treatments that delay the onset or slow down the progression of HD. Our proposed studies will examine the effect of a clinical approved PPAR? agonist on disease onset and progression in mouse models of HD and result in a strategy to develop therapeutics for HD.