Activation of PPAR-gamma in a Monkey Model of Cardiac Dysautonomia

心脏自主神经功能障碍猴模型中 PPAR-γ 的激活

基本信息

批准号：
8835160
负责人：
MARINA EMBORG
金额：
$ 22.17万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835160
关键词：
3-nitrotyrosine Affect Aftercare Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Antidiabetic Drugs Autonomic Dysfunction Biological Markers Biological Preservation Blood Pressure Cardiac Catecholamines Cell Death Chronic Clinical Data Denervation Development Diabetes Mellitus Disease Dose Dysautonomias Electrocardiogram Evaluation Experimental Designs Fatigue Future Goals HLA-DR Antigens Health Heart Human Image Inflammation Injury Intravenous Lesion MPTP Poisoning Measures Mediating Methods Modeling Monkeys Myocardial Nerve Degeneration Neurodegenerative Disorders Neuroprotective Agents Neurotoxins Oral Orthostatic Hypotension Oxidative Stress Oxidopamine PPAR gamma Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Pattern Peripheral Peroxisome Proliferator-Activated Receptors Peroxisome Proliferators Physicians Pioglitazone Positron-Emission Tomography Property Quality of life Sympathectomy Symptoms Technology Testing Therapeutic Effect Time TimeLine Translating Treatment Efficacy Up-Regulation alpha synuclein base clinical application cytokine diabetic falls improved in vivo meta-hydroxyephedrine minimally invasive nerve supply neuroprotection nonhuman primate novel strategies prevent radioligand receptor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Nonmotor symptoms of Parkinson's disease (PD), such as cardiac autonomic dysfunction (dysautonomia), greatly affect patients' quality of life. They are frequently unrecognized as PD symptoms, many times undiagnosed and overall poorly managed, as they do not respond to typical anti-parkinsonian therapies. Progress towards improving treatments and biomarkers have been hampered by the lack of animal models. We have developed a nonhuman primate (NHP) model of cardiac dysautonomia by intravenous delivery of the neurotoxin 6-OHDA and developed a battery of tests to characterize the model. We have also demonstrated that oral dosing of the peroxisome proliferator activator receptor gamma (PPARγ) agonist pioglitazone modulates inflammation and oxidative stress, inducing neuroprotection in a NHP model of PD with typical nigrostriatal degeneration. Based on these studies we hypothesize that pioglitazone can be neuroprotective in the NHP model of cardiac dysautonomia and that the therapeutic effects are mediated via a reduction in inflammation and oxidative stress. To evaluate this hypothesis we propose: Specific Aim 1: To evaluate whether chronic oral dosing of the PPARγ agonist pioglitazone prevents 6-OHDA-induced peripheral catecholaminergic neurodegeneration and downregulates mechanisms of inflammation and oxidative stress in a NHP model of cardiac dysautonomia. We will use state-of-the-art PET imaging and radioligands to evaluate in vivo cardiac markers of catecholaminergic innervation ([C11]MHED), inflammation ([C11]PK11195) and oxidative stress ([61/64Cu]ATSM) before and after treatments. We will correlate the imaging data with clinical measures (ECG, blood pressure, activity), circulating metabolites (e.g.: catecholamines, cytokines and PGCα-1) and morphological data (e.g.: regional myocardial quantification of TH, HLA-DR, nitrotyrosine and alpha synuclein expression), to analyze how the different measures relate to catecholaminergic loss and preservation. These technologies will allow us to evaluate mechanisms of neurodegeneration and neuroprotection while validating biomarkers for clinical application.

描述（由适用提供）：帕金森氏病（PD）的非运动症状，例如心脏自主神经功能障碍（Dysautonomia），极大地影响了患者的生活质量。它们经常被认为是PD症状的，因为它们对典型的抗帕金森氏疗法没有反应，因此很多次未诊断和总体管理不足。缺乏动物模型，阻碍了改善治疗和生物标志物的进展。我们通过静脉输送神经毒素6-OHDA开发了心脏动作障碍的非人类灵长类动物（NHP）模型，并开发了一系列测试以表征该模型。我们还证明，过氧化物组增殖物激活者受体伽马（PPARγ）激动剂吡丙硝唑调节炎症和氧化应激的口服剂量，在具有典型的肿瘤性变性的PD的NHP模型中诱导神经保护作用。基于这些研究，我们假设吡格列酮可以在心脏动作障碍的NHP模型中具有神经保护作用，并且通过减少炎症和氧化物胁迫来介导治疗作用。为了评估这一假设，我们提出：具体目的1：评估PPARγ激动剂吡格列酮的慢性口服剂量是否可以防止6-OHDA诱导的外周theral蛋白儿茶酚胺能神经变性和下调感染和氧化物的机械性和氧化物的机械性，而NHP的心脏dysautonanmia模型我们将使用最先进的PET成像和放射性配体来评估儿茶酚胺能神经的体内心脏标志物（[[C11] MHED），炎症（[C11] PK11195）和氧化应激（[61/64CU]在治疗之前和之后）。 We will correlate the imaging data with clinical measurements (ECG, blood pressure, activity), circulating metabolites (e.g.: catecholamines, cytokines and PGCα-1) and morphological data (e.g.: regional myocardial quantification of TH, HLA-DR, nitrotyrosine and alpha synuclein expression), to analyze how the different measures relate to catecholaminergic loss和保存。这些技术将使我们能够评估神经变性和神经保护的机制，同时验证生物标志物进行临床应用。