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，它的进展是无声的（没有临床表现）