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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

帕金森病 (PD) 是一种无法治愈的神经退行性疾病，会悄无声息地进展（无需临床治疗）绝大多数人在 PD 相关运动功能障碍的首次症状出现前数年。的 PD 病例（约 85%）为特发性（idPD），目前尚无特异性生物标志物用于早期诊断 Bolotina 博士实验室的最新发现（Zhou 等人，《自然》） Communications，2016）导致 PARK14 / PLA2g6- 中先前未知的缺陷的识别依赖性 Ca2+ 信号传导 (PLA2g6/Ca2+)，可在 idPD 患者的外周细胞中检测到，并且可能我们还确定这种缺陷会导致新的生物标志物策略的开发。多巴胺能神经元进行性衰退，并出现年龄依赖性 PD 样运动功能障碍与人类 idPD 非常相似的新小鼠模型重要的是，我们发现人类 idPD 之间存在很强的关联。 PLA2g6(L) 表达/功能显着丧失，并且钙库操纵的 Ca2+ 进入 (SOCE) 受损，我们可以在 idPD 患者试验组的原代皮肤成纤维细胞 (PSF) 中检测到这一点。在这里，我们发现可以利用血小板和/或 PSF 中 PLA2g6/Ca2+ 信号传导的特征缺陷作为检测老年人 IDPD 的新型生物标志物，我们正在寻求一项试点计划的支持。重点验证我们新的基于 PLA2g6/Ca2+ 的生物标志物的特异性，并将测试使用的可行性我们的研究将人类血小板和/或皮肤成纤维细胞中的这些生物标志物作为检测 idPD 的新方法。团队具有独特的资格来开展拟议的研究：Bolotina 博士（PI）拥有独特的知识并建立了在人类受试者试验组中验证 PLA2g6/Ca2+ 生物标志物的实验平台，以及 Saint- Hilaire（临床联合研究员）目前参与帕金森病进展标志物倡议 (PPMI) 研究，并拥有完善的捐赠者招募和样本收集平台。所有方法均已建立和实施。 PI 和合作研究者发表的初步数据完全支持我们的假设并证明了我们的可行性。我们提案的具体目标是：目标 1：使用现有的初级样品验证 idPD 特征性 PLA2g6/Ca2+ 缺陷的特异性来自 NINDS 存储库的皮肤成纤维细胞 PLA2g6(L)、存储操作的 Ca2+ 进入和 ER 的表达和功能。将使用分子、生化和成像技术分析 Ca2+ 水平，并在成纤维细胞中进行比较来自 idPD、家族性 PD（LRRK2 或 GBA 突变）、阿尔茨海默病、亨廷顿病、所有样本均来自 NINDS 人类细胞和数据存储库。目标 2：测试是否可以在 idPD 血小板中检测到 PLA2g6/Ca2+ 信号传导的特征缺陷活血小板和皮肤成纤维细胞样本将从老年患者试点组中获得。被诊断为早期 IDPD，并与年龄匹配的对照组非神经系统捐献者进行比较。 PLA2g6/Ca2+ 信号传导将使用分子、生化和成像技术进行分析。