Parkinson’s disease biomarkers in human olfactory cleft mucus

项目总结 帕金森病(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。帕金森病患者通常在已经出现运动障碍时被诊断为帕金森病患者，表明 黑质中的多巴胺能神经元已经发生了显著的丢失。嗅觉障碍是 帕金森病最早的症状之一，通常发生在运动障碍的前几年。刘易体， 帕金森病的组织病理学特征，在帕金森病的早期阶段积聚在嗅球内。最近的证据 提示路易小体的主要蛋白质成分α-突触核蛋白(α-Syn)可以增殖 进一步提示嗅觉系统在帕金森病中的关键作用 发病机制。然而，到目前为止，还没有对人类嗅觉组织进行全面的检查来识别 帕金森病的分子生物标志物。该R21项目的目标是识别人类嗅裂中的PD生物标记物 粘液。嗅觉感觉神经元集中在鼻子的上鼻甲，将轴突投射到 大脑中的嗅球。我们最近使用人类嗅裂粘液，一种生物流体进行的蛋白质组学研究 覆盖在嗅黏膜表面，鉴定出几种与PD相关的蛋白质， 包括α-Syn、DJ-1和炎性生物标记物。对帕金森病患者队列的初步研究表明 α-SYN/DJ-1比值和某些炎性生物标志物水平显著升高。 帕金森病患者的嗅觉粘液与年龄匹配的对照组的比较。初步数据还显示，α- SYN/DJ-1比值区分PD患者和对照组具有很高的敏感性和特异性，显示 很强的生物标志物潜力。在这里，我们建议招募更多的早期或晚期帕金森病患者 作为年龄匹配的对照组。我们将使用我们研究团队建立的微创方法来收集 嗅裂粘液。我们将进行免疫分析以确定α-Syn、DJ-1和多个 炎性生物标志物。我们将检验α-Syn和DJ-1比率是一个可靠的生物标志物的假设 警察。此外，我们将使用机器学习方法来优化PD的嗅觉生物标记物 进步。这个多学科项目汇集了在嗅觉方面有专长的调查人员，PD 病理学、炎症和机器学习。我们的研究可能会对患者护理产生重大影响 提高帕金森病的早期和准确诊断。

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.