Parkinson’s disease biomarkers in human olfactory cleft mucus

人类嗅裂粘液中的帕金森病生物标志物

• 批准号: 10354673
• 负责人: James Morley
• 金额: $ 20.34万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-04 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354673
• 关键词: Affect; Age; Aging; American; Appearance; Axon; Biological Markers; Biopsy; Brain; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Management; Clinical Trials; Colon; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Elderly; Enrollment; Exhibits; Future; Genes; Goals; Homeostasis; Human; Immunoassay; Inflammation; Inflammatory; Inherited; Lewy Bodies; Lewy body pathology; Lewy neurites; Longitudinal Studies; Machine Learning; Measurable; Methods; Modification; Molecular; Molecular Biology; Molecular Chaperones; Mucous body substance; Mutation; Nasal turbinate bone structure; Neurodegenerative Disorders; Neurons; Nose; Olfactory Epithelium; Olfactory Mucosa; Olfactory Pathways; Olfactory dysfunction; Onset of illness; Oxidation-Reduction; PARK7 gene; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patient Care; Patients; Peripheral; Play; Process; Proteins; Proteomics; ROC Curve; Research; Research Personnel; Risk Factors; Role; Salivary Glands; Sensitivity and Specificity; Severity of illness; Signal Transduction; Site; Smell Perception; Solid; Source; Specificity; Substantia nigra structure; Surface; Symptoms; Techniques; Testing; Tissues; accurate diagnosis; alpha synuclein; alpha synuclein gene; clinical diagnosis; cohort; cytokine; diagnostic biomarker; disease diagnosis; disorder risk; dopaminergic neuron; early onset; illness length; improved; individual patient; inflammatory marker; loss of function mutation; machine learning algorithm; minimally invasive; molecular marker; motor deficit; motor symptom; multidisciplinary; novel; olfactory bulb; olfactory sensory neurons; pre-clinical; predictive marker; prevent; protein aggregation; protein biomarkers; public health relevance; recruit; therapy development; trend; Affect; Age; Aging; American; Appearance; Axon; Biological Markers; Biopsy; Brain; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Management; Clinical Trials; Colon; Complex; Data; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Elderly; Enrollment; Exhibits; Future; Genes; Goals; Homeostasis; Human; Immunoassay; Inflammation; Inflammatory; Inherited; Lewy Bodies; Lewy body pathology; Lewy neurites; Longitudinal Studies; Machine Learning; Measurable; Methods; Modification; Molecular; Molecular Biology; Molecular Chaperones; Mucous body substance; Mutation; Nasal turbinate bone structure; Neurodegenerative Disorders; Neurons; Nose; Olfactory Epithelium; Olfactory Mucosa; Olfactory Pathways; Olfactory dysfunction; Onset of illness; Oxidation-Reduction; PARK7 gene; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patient Care; Patients; Peripheral; Play; Process; Proteins; Proteomics; ROC Curve; Research; Research Personnel; Risk Factors; Role; Salivary Glands; Sensitivity and Specificity; Severity of illness; Signal Transduction; Site; Smell Perception; Solid; Source; Specificity; Substantia nigra structure; Surface; Symptoms; Techniques; Testing; Tissues; accurate diagnosis; alpha synuclein; alpha synuclein gene; clinical diagnosis; cohort; cytokine; diagnostic biomarker; disease diagnosis; disorder risk; dopaminergic neuron; early onset; illness length; improved; individual patient; inflammatory marker; loss of function mutation; machine learning algorithm; minimally invasive; molecular marker; motor deficit; motor symptom; multidisciplinary; novel; olfactory bulb; olfactory sensory neurons; pre-clinical; predictive marker; prevent; protein aggregation; protein biomarkers; public health relevance; recruit; therapy development; trend

PROJECT SUMMARY Early diagnosis of Parkinson’s disease (PD) remains a big challenge, as clinicians are still lacking reliable biomarkers. PD patients are typically diagnosed when they have already developed motor deficits, indicating significant loss of dopaminergic neurons in the substantia nigra has already occurred. Olfactory impairment is one of the earliest symptoms of PD, often occurring several years before motor deficits. Lewy bodies, the histopathological hallmarks of PD, accumulate in the olfactory bulb in early stages of PD. Recent evidence indicates that aberrant α-synuclein (α-Syn), the main protein component of Lewy bodies, can propagate transneuronally from the olfactory bulb, further suggesting the critical role of the olfactory system in PD pathogenesis. However, to date, human olfactory tissue has not been comprehensively examined to identify molecular biomarkers for PD. The goal of this R21 project is to identify PD biomarkers in human olfactory cleft mucus. Olfactory sensory neurons are concentrated in the superior turbinate of the nose, projecting axons to the olfactory bulb in the brain. Our recent proteomics studies using human olfactory cleft mucus, a biofluid covering the surface of the olfactory mucosa, identified several well-established PD-associated proteins, including α-Syn, DJ-1, and inflammatory biomarkers. Preliminary studies of a PD patient cohort showed that the ratio of α-Syn to DJ-1 and levels of certain inflammatory biomarkers are substantially elevated in the olfactory mucus of PD patients compared to age-matched controls. Preliminary data also showed that the α- Syn/DJ-1 ratio distinguishes PD patients from control subjects with high sensitivity and specificity, showing strong biomarker potential. Here we propose to recruit additional patients with early or advanced PD, as well as age-matched controls. We will use a minimally invasive method established by our research team to collect olfactory cleft mucus. We will conduct immunoassays to determine levels of α-Syn, DJ-1, and multiple inflammatory biomarkers. We will test the hypothesis that the ratio of α-Syn to DJ-1 is a reliable biomarker for PD. Furthermore, we will use machine learning approaches to optimize olfactory biomarkers for PD progression. This multidisciplinary project brings together investigators with expertise in olfaction, PD pathology, inflammation, and machine learning. Our research may have a major impact on patient care by improving early and accurate diagnosis of PD.

项目摘要 帕金森氏病（PD）的早期诊断仍然是一个巨大的挑战，因为临床医生仍然缺乏可靠的 生物标志物。 PD患者通常在已经开发电机定义时被诊断出来，表明 尼格拉底虫中的多巴胺能神经元显着丧失。嗅觉障碍是 PD最早的症状之一，通常发生在电动机定义前几年。路易的身体， PD的组织病理学标志在PD的早期阶段积聚在嗅球中。最近的证据 表明异常的α-突触核蛋白（α-syn）是路易体的主要蛋白质成分，可以传播 从嗅球的透射式神经元，进一步表明嗅觉系统在PD中的关键作用 发病。但是，迄今为止，尚未对人类嗅觉组织进行全面检查以识别 PD的分子生物标志物。这个R21项目的目的是识别人类嗅觉裂口中的PD生物标志物 粘液。嗅觉感觉神经元集中在鼻子的上涡轮上，将轴突投射到 大脑中的嗅球。我们最近使用人类嗅觉裂口粘液的蛋白质组学研究，一种生物流体 覆盖嗅觉粘膜的表面，确定了几种公认的PD相关蛋白， 包括α-Syn，DJ-1和炎症生物标志物。 PD患者队列的初步研究表明 在 与年龄匹配的对照相比，PD患者的嗅觉粘液。初步数据还表明α- SYN/DJ-1比例将PD患者与具有高灵敏度和特异性的对照受试者区分开 强大的生物标志物潜力。在这里，我们建议招募其他早期或高级PD患者 作为年龄匹配的控件。我们将使用我们的研究团队建立的微创方法来收集 嗅觉裂缝粘液。我们将进行免疫测定以确定α-Syn，DJ-1和多个的水平 炎症生物标志物。我们将测试以下假设：α-Syn与DJ-1的比率是可靠的生物标志物 PD。此外，我们将使用机器学习方法来优化PD嗅觉生物标志物 进展。这个多学科项目将研究人员汇集到嗅觉方面的专业知识，PD 病理，感染和机器学习。我们的研究可能会对患者护理产生重大影响 改善PD的早期和准确诊断。