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

• 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
• 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

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 这一提议建立在数十年来支持线粒体功能障碍的关键作用的证据基础上， 神经退行性疾病中的炎症。该提案的目标是评估线粒体的潜力 压力信号作为帕金森病（PD）进展的预测生物标志物。我们的假设是 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 释放免疫原性压力信号，驱使衰老的大脑进入促炎状态。如果这些压力 信号未得到解决，高危受试者的氧化应激将持续升高，高于 神经退行性变的阈值，最终导致PD的临床表现。到目前为止，最早和 在PD中最确定的线粒体应激信号是活性氧（ROS）的产生。的一个关键 线粒体ROS的信号传导功能是警告细胞环境即将发生的生物能量应激。 线粒体ROS直接激活小胶质细胞，并增强其他线粒体损伤的免疫原性 相关模式（mtDAMP）和α-突触核蛋白在风险PD脑。应激产生的主要活性氧 线粒体和活化的小胶质细胞是超氧化物（O2*-）。因此，O2*-提供了线粒体的信号， 免疫（线粒体免疫）应激。我们将确定这种有丝分裂免疫信号是否是PD的关键驱动因素， 首个血脑屏障渗透性、O2* 选择性PET探针，可从关键部位追踪体内PD进展 在不同的动物模型中，前驱期特征一直持续到结束阶段。我们的初步结果支持这一假设 有风险的PD受试者具有增加的基础氧化应激水平，其1）可通过[18 F]ROStrace检测， 2)与PD进展相关，和3）使转基因动物对与PD相关的毒素敏感。我们现在 我建议在已建立的PD小鼠模型中验证这些发现， 线粒体免疫应激和α-突触核蛋白病理学。将监测前驱症状的进展 通过PET/MRI、睡眠-觉醒动力学和情绪行为测试， 嗅觉、认知和自主功能，在多巴胺能神经元损失引起的运动损伤之前。 这种方法将使我们能够研究线粒体免疫信号传导在模拟细胞凋亡的条件下的作用。 PD发病机制的复杂性在大多数迟发性患者。我们的多层次、高度可转换的战略 旨在确保这项研究直接应用于临床。