Superoxide-sensitive radiotracer as a predictive biomarker of Parkinson's disease progression

超氧化物敏感放射性示踪剂作为帕金森病进展的预测生物标志物

基本信息

批准号：
10320367
负责人：
Meagan Joy McManus
金额：
$ 51.4万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320367
关键词：
Address Age Aging Animal Model Attenuated Automobile Driving Autonomic Dysfunction Bioenergetics Biological Markers Blood - brain barrier anatomy Brain Brain Diseases Cells Clinic Clinical Clinical Trials Design Cognition Disease Disease Progression Disease model Dopamine Early Diagnosis Ensure Environment Environmental Risk Factor Functional disorder Future Genetic Risk Goals Homeostasis Image Immune Immune signaling Individual Inflammation Inflammatory Lewy Body Dementia Link Lipopolysaccharides Magnetic Resonance Imaging Measures Mediator of activation protein Microglia Mitochondria Modeling Molecular Monitor Moods Mus Mutation NADPH Oxidase Nerve Degeneration Neurodegenerative Disorders Organelles Outcome Oxidative Stress Oxides Parkinson Disease Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phase Phenotype Positron-Emission Tomography Production Reactive Oxygen Species Research Risk Risk Factors Role Signal Transduction Sleep Sleep Wake Cycle Smell Perception Source Stimulus Stress Superoxides Susceptibility Gene System Testing Therapeutic Therapeutic Intervention Toxin Transgenic Animals Transgenic Organisms Treatment Efficacy Work acetovanillone aging brain alpha synuclein base behavior test clinical application clinical biomarkers clinically relevant design direct application disease diagnosis dopaminergic neuron gene product hyposmia immune activation immunogenic immunogenicity in vivo inhibitor insight mitochondrial dysfunction mitopark mouse motor disorder motor impairment mouse model neuroinflammation neuron loss novel predictive marker pressure radiotracer response targeted biomarker translatable strategy

项目摘要

PROJECT SUMMARY This proposal builds on decades of evidence supporting a crucial role for mitochondrial dysfunction and inflammation in neurodegenerative disease. The goal of this proposal is to evaluate the potential of mitochondrial stress signals as predictive biomarkers of Parkinson’s disease (PD) progression. Our working hypothesis is that collective pressure from genetic and environmental risk factors impinges on mitochondrial homeostasis, inducing the release of immunogenic stress signals that drive the aging brain into a pro-inflammatory state. If these stress signals are not resolved, at-risk subjects will have a persistent elevation of oxidative stress that is above the threshold for neurodegeneration, ultimately leading to the clinical manifestation of PD. To date, the earliest and most established mitochondrial stress signal in PD is reactive oxygen species (ROS) production. One of the key signaling functions of mitochondrial ROS is to alert the cellular environment of impending bioenergetic stress. Mitochondrial ROS directly activate microglia, and boost the immunogenicity of other mitochondrial damage associated patterns (mtDAMPs) and α-synuclein in the at-risk PD brain. The primary ROS produced by stressed mitochondria and activated microglia is superoxide (O2*-). Thus, O2*- provides a signal of mitochondrial and immune (mito-immune) stress. We will determine if this mito-immune signal is a critical driver of PD using the first blood-brain barrier permeant, O2*- selective PET probe to track PD progression in vivo from the key prodromal features to the end stages in distinct animal models. Our preliminary results support the hypothesis that at-risk PD subjects have increased basal levels of oxidative stress that are 1) detectable by [18F]ROStrace, 2) correlate with PD progression, and 3) sensitize transgenic animals to toxins associated with PD. We now propose to validate these findings in established PD mouse models with prodromal features specifically related to mito-immune stress and α-synuclein pathology. The progression of the prodromal features will be monitored by changes in dopaminergic signaling via PET/MRI, sleep-wake dynamics, and behavioral tests of mood, olfaction, cognition, and autonomic function, prior to motor impairment caused by loss of dopaminergic neurons. This approach will allow us to investigate the role of mito-immune signaling in conditions mimicking the complexity of PD pathogenesis in the majority of late-onset patients. Our multi-tiered, highly translatable strategy is designed to ensure direct application of this research to the clinic.

项目摘要该提议建立在数十年的证据基础上，支持线粒体功能障碍和神经退行性疾病的炎症。该建议的目的是评估线粒体的潜力应力信号是帕金森氏病（PD）进展的预测生物标志物。我们工作的假设是来自遗传和环境风险因素的集体压力影响线粒体稳态，诱导免疫应激信号的释放，这些信号使大脑衰老成为促炎性状态。如果这些压力信号无法解决，处于危险的受试者将具有氧化应激的持续升高神经变性的阈值，最终导致PD的临床表现。迄今为止，最早的 PD中大多数已建立的线粒体应力信号是活性氧（ROS）产生。关键之一线粒体ROS的信号传导功能是提醒即将发生生物能应力的细胞环境。线粒体ROS直接激活小胶质细胞，并提高其他线粒体损伤的免疫原性高危PD脑中的相关模式（mTDAMP）和α-突触核蛋白。由应力产生的主要ROS 线粒体和活化的小胶质细胞是超氧化物（O2* - ）。 o2* - 提供了线粒体和免疫（MITO-免疫）应力。我们将确定使用该MITO-免疫信号是使用PD的关键驱动程序第一个血脑屏障渗透性，O2* - 选择性PET探针从钥匙中跟踪体内PD进展末端阶段的前驱特征在不同的动物模型中。我们的初步结果支持假设高危PD受试者具有增加的氧化应激水平，这是1）[18f] rostrace可检测的氧化应激水平， 2）与PD进展相关，3）对与PD相关的毒素敏感的转基因动物。我们现在提议在具有前驱特征的已建立的PD鼠标模型中验证这些发现特别相关用于MITO-免疫应激和α-突触核蛋白病理学。前驱特征的进展将受到监控通过通过PET/MRI，睡眠效果动力学和情绪的行为测试的多巴胺能信号传导的变化，嗅觉，认知和自主功能，在因多巴胺能神经元丧失引起的运动障碍之前。这种方法将使我们能够研究Mito-rumune信号在模仿的条件下的作用大多数晚期患者的PD发病机理的复杂性。我们的多层，高度翻译的策略旨在确保将该研究直接应用于诊所。