PARK14/Calcium signaling as a novel biomarker for Parkinson disease

PARK14/钙信号传导作为帕金森病的新型生物标志物

• 批准号: 9379694
• 负责人: Victoria M Bolotina
• 金额: $ 25.33万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9379694
• 关键词: Age; Aging; Alzheimer' s Disease; Biochemical; Biological Markers; Biopsy; Blood Platelets; Calcium Signaling; Cells; Clinical; Communication; Control Groups; Data; Databases; Defect; Detection; Development; Diagnosis; Disease; Early Diagnosis; Early Intervention; Fibroblasts; Future; Goals; Human; Huntington Disease; Idiopathic Parkinson Disease; Imaging Techniques; Impairment; Knowledge; LRRK2 gene; Lead; Matched Group; Molecular; Mutation; National Institute of Neurological Disorders and Stroke; Nature; Neurodegenerative Disorders; Outcome; Parkinson Disease; Pathogenicity; Patients; Pattern; Peripheral; Plasma; Population; Process; Publishing; Recruitment Activity; Reproducibility; Research; Research Personnel; Risk; Saints; Sampling; Signal Transduction; Skin; Specificity; Specimen; Symptoms; Testing; Validation; age group; age related; alpha synuclein; base; biomarker development; disorder control; dopaminergic neuron; early detection biomarkers; fight against; human subject; motor disorder; mouse model; neuron development; novel; novel marker; novel strategies; peripheral blood; programs; progression marker; repository; sample collection; screening; specific biomarkers

Parkinson’s disease (PD) is an incurable neurodegenerative disorder that progresses silently (without clinical manifestations) for years prior to onset of the first symptoms of PD-associated motor dysfunction. The vast majority of PD cases (about 85%) are idiopathic (idPD), and currently, there are no specific biomarkers for early diagnosis of this devastating disease in aging humans. Recent discoveries in Dr. Bolotina’s lab (Zhou et al, Nature Communications, 2016) resulted in identification of the previously unknown defect(s) in PARK14 / PLA2g6- dependent Ca2+ signaling (PLA2g6/Ca2+), which could be detected in peripheral cells from idPD patients, and may be used for development of a brand new biomarker strategy. We also established that such defects lead to progressive demise of dopaminergic neurons and development of age-dependent PD-like motor dysfunction in a new mouse model that closely mimics idPD in humans. Importantly, we found a strong association of human idPD with significant loss of PLA2g6(L) expression/function and impairment of the store-operated Ca2+ entry (SOCE), which we could detect in primary skin fibroblasts (PSFs) from a pilot group of idPD patients. Here we hypothesize that signature defects in PLA2g6/Ca2+ signaling in platelets and/or PSFs could be used as a novel biomarker for detection of idPD in aging humans. We are seeking support for a pilot program that will focus on validation of the specificity of our new PLA2g6/Ca2+-based biomarker, and will test the feasibility of using these biomarkers in human platelets and/or skin fibroblasts as a novel approach for detection of idPD. Our research team is uniquely qualified for proposed studies: Dr. Bolotina (PI) has unique knowledge and established experimental platform for validation of PLA2g6/Ca2+ biomarkers in the pilot groups of human subjects, and Dr. Saint- Hilaire (clinical Co-Investigator) is currently involved in the Parkinson’s Progression Markers Initiative (PPMI) study, and has a well-established platform for donor recruitment and sample collection. All approaches are established and published by PI and Co-Investigator. Preliminary data fully support our hypothesis and demonstrate feasibility of our proposal. Specific Aims of our proposal are: Aim 1: To validate specificity of the signature PLA2g6/Ca2+ defects for idPD using existing samples of primary skin fibroblasts from NINDS repository. Expression and function of PLA2g6(L), store-operated Ca2+ entry and ER Ca2+ levels will be analyzed using molecular, biochemical, and imaging techniques, and compared in fibroblasts from the patients with idPD, familial PD (mutations in LRRK2 or GBA), Alzheimer’s disease, Huntington’s disease, and control non-neurologic donors. All samples will be obtained from NINDS human cell and data repository. Aim 2: To test if the signature defects in PLA2g6/Ca2+ signaling could be detected in platelets from idPD patients. The samples of live platelets and skin fibroblasts will be obtained from a pilot group of aged patients diagnosed with early stages of idPD, and compared with the age-matched group of control non-neurologic donors. PLA2g6/Ca2+ signaling will be analyzed using molecular, biochemical, and imaging techniques.

帕金森氏病（PD）是一种无法治愈的神经退行性疾病，默默发展（没有临床 表现形式）在发作PD相关运动功能障碍的第一个症状之前多年。绝大多数 PD病例（约85％）是特发性（IDPD），目前没有特定的生物标志物可以早期诊断 这种毁灭性的疾病在衰老的人类中。 Bolotina博士实验室的最新发现（Zhou等人，自然 Communications，2016年）导致识别PARK14 / PLA2G6-的先前未知缺陷 依赖性Ca2+信号传导（PLA2G6/Ca2+），可以在IDPD患者的外围细胞中检测到，并且可以 用于制定全新的生物标志物策略。我们还确定，这种缺陷导致 多巴胺能神经元的逐渐消亡和年龄依赖性PD运动功能障碍的发展 紧密模仿人类IDPD的新鼠标模型。重要的是，我们发现了人类IDPD的密切关联 PLA2G6（L）表达/功能的显着损失以及储存的CA2+进入（SOCE）的损害， 我们可以在IDPD患者试点的初级皮肤成纤维细胞（PSF）中检测到。 在这里，我们假设可以使用PLA2G6/Ca2+信号传导中的签名缺陷和/或PSF。 作为在衰老人类中检测IDPD的新型生物标志物。我们正在寻求支持试点计划的支持 专注于验证我们的新PLA2G6/Ca2+基于生物标志物的特异性，并将测试使用的可行性 这些生物标志物在人血小板和/或皮肤成纤维细胞中是一种新型的IDPD检测方法。我们的研究 团队具有独特的资格进行拟议的研究：Bolotina博士（PI）具有独特的知识并建立了 在人类受试者试点组中验证PLA2G6/CA2+生物标志物的实验平台，Saint-博士 Hilaire（临床共同研究器）目前参与了帕金森的进步标记倡议（PPMI）研究， 并设有一个完善的平台，用于捐助和样本收集。建立了所有方法， 由PI和共同研究者出版。初步数据完全支持我们的假设并证明了我们的可行性 提议。我们提案的具体目的是： 目的1：验证使用主要样本的IDPD的签名PLA2G6/Ca2+缺陷的特异性 Ninds存储库的皮肤成纤维细胞。 PLA2G6（L）的表达和功能，商店经营的Ca2+进入和ER CA2+水平将使用分子，生化和成像技术进行分析，并在成纤维细胞中进行比较 来自IDPD的患者，家族性PD（LRRK2或GBA中的突变），阿尔茨海默氏病，亨廷顿氏病， 并控制非神学捐助者。所有样品将从Ninds人类细胞和数据存储库中获得。 目标2：测试是否可以在IDPD的血小板中检测到PLA2G6/Ca2+信号传导中的签名缺陷。 患者。活血小板和皮肤成纤维细胞的样品将从老年患者的试点组中获得 被诊断为IDPD的早期阶段，并与年龄匹配的对照非神经学供体进行了比较。 PLA2G6/CA2+信号将使用分子，生化和成像技术分析。