Analysis of Olfactory Dysfunction for Early Diagnosis of Parkinson's Disease

嗅觉障碍对帕金森病早期诊断的分析

• 批准号: 9137152
• 负责人: ROBERT A CLARK
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137152
• 关键词: Address; Age; Age-Years; American; Animal Model; Axon; Behavioral; Biochemical; Biological Markers; Brain; Breeding; Cellular Morphology; Code; Cognitive; Confocal Microscopy; Consensus; Demographic Aging; Dendrites; Deposition; Deterioration; Diagnosis; Diagnostic; Discrimination; Disease; Disease Outcome; Disease Progression; Early Diagnosis; Economic Burden; Electron Microscopy; Enrollment; Epidemiologic Studies; Etiology; Event; Exposure to; Face; Family; Functional Magnetic Resonance Imaging; Functional disorder; Funding Opportunities; Genetic; Genetic Models; Histology; Human; Idiopathic Parkinson Disease; Imaging technology; Injury; Internal Ribosome Entry Site; Interneurons; Knowledge; LacZ Genes; Lead; Link; Magnetic Resonance Imaging; Manganese; Maps; Measurable; Methods; Military Personnel; Modality; Modeling; Monitor; Morbidity - disease rate; Motor; Mouse Protein; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; Odorant Receptors; Odors; Olfactory Pathways; Oxidative Stress; Parkinson Disease; Pathologic; Pathway interactions; Patients; Pattern; Phase; Play; Population; Prevalence; Proteins; Research; Resolution; Risk; Risk Factors; Role; Sensory; Signal Transduction; Smell Perception; Societies; Sorting - Cell Movement; Staging; Structure; Synapses; System; Therapeutic; Time; Toxic effect; Transgenic Mice; Veterans; alpha synuclein; awake; base; cognitive task; cost; disease diagnosis; disorder risk; dopaminergic neuron; in vivo; innovation; insight; interest; mitral cell; mortality; neural circuit; neurobehavioral test; neuroimaging; novel therapeutics; olfactory bulb; olfactory bulb glomeruli; olfactory sensory neurons; population based; pre-clinical; prospective; public health relevance; research study; synuclein; synucleinopathy; tau Proteins; tool

 DESCRIPTION (provided by applicant): Of the challenges that face Parkinson's disease (PD) research, few are more pressing than early detection of preclinical disease. Currently no method exists to diagnose PD before the irreversible deterioration of the brain. The lack of useful biomarkers is also a roadblock for studies of disease-modifying therapies, leading to the strong consensus that a major initiative to develop PD biomarkers is essential. Sense of smell is among the first casualties of PD, with olfactory loss occurring in up to 90% of patients. Furthermore, an association between impaired olfaction and subsequent PD diagnosis has been found in prospective population-based studies, suggesting that olfactory dysfunction is a very early sign of idiopathic PD. Although interest in using olfaction as a biomarker for PD has increased substantially in recent years, the mechanism of olfactory loss and its cause-and-effect relationship to -synucleinopathy, a major pathological hallmark of PD, remain unclear. This knowledge gap has created a major roadblock to diagnostic and therapeutic progress. Thus, it is critical that we understand the olfactory system neuroanatomical changes that lead to loss of smell in both the preclinical and symptomatic phases of PD, since an understanding of this pathway in well-defined animal models would significantly impact our knowledge of the mechanisms for loss of dopaminergic neurons, and at the same time provide a means for rapid and objective assessment of disease risk. Our over-arching hypothesis is that olfactory damage in PD is an early event based on specific neuroanatomical changes with measurable functional impact, and is directly linked to upstream -synuclein toxicity. We will assess the olfactory system by capitalizing on a well-established murine genetic model of PD, namely α-synuclein aggregate deposition in mThy1-hSNCA transgenic mice, and emphasizing experiments during the prodromal stage. This model is highly relevant to the etiology of olfactory dysfunction in human PD owing to its construct and face validity with PD in humans. Moreover, we will achieve high-level definition of olfactory system injury by exploiting: i) tagged odorant receptor-expressing transgenic mice (M72- or P2-IRES- tau-LacZ) for precise tracking of olfactory sensory neurons (OSNs) and their stereotypic olfactory sensory map, ii) thy1-yellow fluorescent protein (YFP) transgenic mice for analyzing mitral cells, their neural circuitry and archicortical projections, and iii) advanced non-invasive functional neuroimaging (fMRI, MEMRI, and GT-tMRI). By combining these incisive modalities with behavioral, biochemical, and histological assessments, we will elucidate the neuroanatomical substrate for early olfactory loss in PD, while also addressing the role of synucleinopathy in PD-associated olfactory dysfunction. Three aims are proposed: Aim 1 - To understand the role of post-synaptic -synuclein toxicity in structural and functional changes in the olfactory sensory neurons and their stereotypic olfactory sensory map leading to impaired sense of smell in PD. Aim 2 - To elucidate how abnormal -synuclein aggregates induce structural changes in the olfactory bulb mitral cells, their neural circuitry and modulatory interneurons, leading to impaired sense of smell in PD. Aim 3 - To elucidate how abnormal -synuclein aggregates alter archicortical projections and targets of mitral cells leading to impaire odor identification and discrimination in PD. These studies are significant, as the results will enhance understanding of the mechanisms of olfactory loss in PD and its relationship to pathologic -synuclein. Our results will in turn provide clues to new therapies, as well as biomarkers useful for early detection, prognostication, and monitoring of either disease progression or outcomes of disease-modifying therapies. Our approaches are innovative, since they exploit incisive genetic and cutting-edge analytic tools, and the study is highly feasible due to the team's expertise in olfaction, PD, neurodegeneration, oxidative stress, neurobehavioral testing, and advanced imaging technologies.

 描述（由申请人提供）： 在面对帕金森氏病（PD）研究面临的挑战中，很少有紧迫的临床前疾病。当前，在不可逆测定大脑之前，尚无诊断PD的方法。缺乏有用的生物标志物也是研究疾病改良疗法的障碍，这使得强烈共识是，开发PD生物标志物的主要举措至关重要。嗅觉是PD的第一批人员伤亡之一，嗅觉损失多达90％。此外，在基于人群的前瞻性研究中发现了嗅觉受损与随后的PD诊断之间的关联，这表明嗅觉功能障碍是特发性PD的早期迹象。尽管在近年来使用嗅觉作为PD的生物标志物方面很有趣，但嗅觉损失的机制及其与-突触核酸的因果关系的机制（PD的主要病理标志）尚不清楚。这种知识差距为诊断和治疗进展带来了重大的障碍。这是至关重要的是，我们了解嗅觉系统神经解剖学变化，导致PD的临床前和症状阶段丧失气味，因为在明确定义的动物模型中对这一途径的理解会极大地影响我们对多巴胺能神经元的机制的了解，并同时提供疾病的丧失疾病的方法。我们的架构假设是，PD中的嗅觉损害是一个基于特定神经解剖学的早期事件，具有可测量的功能影响，并且直接与上游-突出核蛋白毒性有关。我们将通过对PD的公认的鼠遗传模型（即MTHY1-HSNCA转基因小鼠中的α-突触核蛋白聚集沉积）进行屈服，并强调前驱阶段的实验。该模型与人类PD的嗅觉功能障碍的病因高度相关，因为它的构建和面部有效性在人类中与PD相关。此外，我们将通过利用来实现嗅觉系统损伤的高级定义：i）标记的气味受体表达的转基因小鼠（M72-或P2-ires-tau-lacz），以精确跟踪嗅觉感觉神经元（OSN）及其刻板型嗅觉的感觉式triment trience trorestect ty thy thy1 yelly thy yelly thy yellower Meftery Map，分析了二尖瓣细胞，神经记录和存档的投影，以及iii）晚期非侵入性功能神经影像学（fMRI，MEMRI和GT-TMRI）。通过将这些敏锐的模态与行为，生化和组织学评估相结合，我们将阐明神经解剖学底物在PD中早期嗅觉损失，同时还针对伴核核酸词在PD嗅觉相关功能障碍中的作用。提出了三个目的：目标1-了解后突触后 - 突触核蛋白毒性在结构和功能变化中的作用 嗅觉感觉神经元及其刻板印象的嗅觉感觉图导致PD中的嗅觉受损。目的2-阐明异常突触核蛋白如何影响嗅球二尖瓣细胞的结构变化，它们的神经元电路和调节性中间神经元，从而导致PD中的气味受损。目的3-阐明异常突出核蛋白聚集体如何改变二尖瓣细胞的存档投影和靶标，从而损害PD中的气味鉴定和歧视。这些研究很重要，因为结果将增强对PD嗅觉损失机制及其与病理核蛋白的关系的理解。我们的结果反过来又将为新疗法提供线索，以及生物标志物，可用于早期检测，提示和监测疾病进展或疾病改良疗法的结果。我们的方法是创新的，因为它们利用了敏锐的遗传和尖端分析工具，这项研究是高度可行的 授予团队在嗅觉，PD，神经退行性，氧化应激，神经行为测试和高级成像技术方面的专业知识。