Early Onset Parkinson’s disease subtypes and pathogenic mechanisms

早发性帕金森病亚型及致病机制

• 批准号: 10719645
• 负责人: Giulietta Maria Riboldi
• 金额: $ 71.45万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719645
• 关键词: Accounting; Address; Affect; Age; Age of Onset; Architecture; Biochemical; Biological Assay; Biological Markers; Biopsy; Brain; Categories; Cells; Cerebrospinal Fluid; Clinical; Clinical Data; Clinical Trials; Clinical stratification; Cluster Analysis; Counseling; Data; Data Correlations; Diagnostic; Disease; Early identification; Eligibility Determination; Failure; Family; Family member; Frequencies; Genes; Genetic; Genetic Counseling; Genetic Diseases; Goals; Healthcare Systems; Immune; Immune system; Incidence; Inflammation; Inflammatory; Japan; Knowledge; LRRK2 gene; Life; Onset of illness; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Patients; Peripheral; Persons; Phenotype; Play; Population; Preventive treatment; Productivity; Proteins; Proteomics; Public Health; Research; Research Proposals; Role; Skin; Therapeutic; Therapeutic Trials; Western World; adaptive immunity; alpha synuclein; career; clinical subtypes; cohort; defined contribution; design; disease prognosis; disorder subtype; early onset; genetic analysis; genetic risk assessment; genetic variant; genome sequencing; immune activation; improved; inflammatory marker; innovation; insight; patient stratification; patient subsets; peripheral blood; precision medicine; prognostic; rare condition; single cell analysis; social; synucleinopathy; therapy design; transcriptomics; trial design; whole genome

ABSTRACT Parkinson’s disease is an umbrella of different subtypes that manifest with distinct clinical features and different underlying pathogenic mechanisms. Genetics, inflammation, and accumulation of alpha-synuclein are the main pathogenic drivers of the disease, playing a different role in sub-groups of patients. Stratifying patients based on the main pathogenic mechanisms is becoming key in the scenario of precision medicine. Extensive characterization of the role of these pathogenic mechanisms in early onset Parkinson’s disease (EOPD) is lacking. EOPD is a rare condition where PD manifests in patients before the age of 50 years and thus affecting large part of the lives of these subjects. Our central hypothesis is that EOPD implies different sub-types of patients with prognostic outcomes related to diverse contribution of genetics, inflammation and alpha-synuclein accumulation in their pathogenesis. The overall objective of this proposal will be to characterize the contribution of genetics, inflammation, and alpha-synuclein accumulation in large cohort of EOPD and assess how these mechanisms can guide the identification of EOPD sub-types. To achieve this objective the main aims of this proposal will focus on 1) characterizing the clinical and genetic profile of a large cohort of EOPD; 2) assessing the presence of alpha-synuclein in central and peripheral biosamples; 3) profiling the central and peripheral inflammatory activation of EODP compared to late onset PD (LOPD) and non-affected subjects (CTRL). For the first aim we will perform a deep phenotypical characterization of a population of EOPD patients and identify phenotypical clusters through an unbiased hierarchical cluster analysis. Subjects will also be profiled genetically through Whole Genome Sequencing (WGS) for the identification of known and new genetic variants, and for burden analysis of rare gene variants. In the second aim we will assess alpha-synuclein amplification assay, one of the most promising innovative biomarkers for synucleinopathy, on skin biopsies and CSF of subjects with EOPD. In the third aim we will characterize the expression profiles of single cells data and an extensive proteomic panel for inflammatory markers from peripheral blood and cerebrospinal fluid of EOPD, LOPD and CTRL, to determine inflammatory activation in EOPD and characterize cell-specific (innate vs adaptive immunity). Finally, we will correlate data from the three aims to assess the profiles of genetics, clinical, inflammatory, and biomarkers data in EOPD sub-types. While most of the current research on this topic focuses on single aspects of the disease, this research proposal is innovative because it correlates different disease mechanisms to detect subtypes of EOPD. The main significance of this project will be to provide new insights in the pathogenesis of EOPD which will be informative to the design of mechanism-driven therapeutic approaches for EOPD, provide useful information for patient counseling, and stratify patients for clinical trials.

摘要 帕金森病是一种不同亚型的总称，表现出不同的临床特征和不同的神经功能。 潜在的致病机制遗传、炎症和α-突触核蛋白的积累是主要原因 疾病的致病驱动因素，在患者的亚组中发挥不同的作用。根据以下因素对患者进行分层 主要的致病机制正在成为精准医疗的关键。广泛 这些致病机制在早发性帕金森病（EOPD）中的作用的表征是 缺乏EOPD是一种罕见的疾病，其中PD在50岁之前的患者中表现出来，因此影响了患者的健康。 这些人的大部分生活。我们的中心假设是，EOPD意味着不同的亚型， 预后结局与遗传、炎症和α-突触核蛋白的不同贡献相关的患者 在其发病机制中积累。本提案的总体目标是确定捐助的特点， 遗传学，炎症，和α-突触核蛋白积累在大队列的EOPD，并评估如何这些 机制可以指导EOPD亚型的鉴定。为了实现这一目标， 该提案将侧重于1）描述大型EOPD队列的临床和遗传特征; 2）评估 中枢和外周生物样品中α-突触核蛋白的存在; 3）对中枢和外周生物样品进行分析， 与晚发型PD（LOPD）和未受影响的受试者（CTRL）相比，EODP的炎症活化。为 我们的第一个目标是对EOPD患者群体进行深入的表型表征， 表型聚类通过无偏的层次聚类分析。还将对受试者进行基因分析 通过全基因组测序（WGS）鉴定已知和新的遗传变异， 罕见基因变异的负担分析。在第二个目标中，我们将评估α-突触核蛋白扩增测定， 最有前途的创新生物标志物的突触核蛋白病，对皮肤活检和CSF的受试者， EOPD。在第三个目标中，我们将表征单细胞数据的表达谱和广泛的蛋白质组学分析。 来自EOPD、LOPD和CTRL的外周血和脑脊液的炎症标志物组， 确定EOPD中的炎症激活并表征细胞特异性（先天性免疫与适应性免疫）。 最后，我们将从这三个目标中关联数据，以评估遗传学、临床、炎症和 EOPD亚型中的生物标志物数据。而目前对这一问题的研究大多集中在单一的方面 这项研究提案是创新的，因为它将不同的疾病机制联系起来， EOPD的亚型。该项目的主要意义将是提供新的见解的发病机制， EOPD将为EOPD机制驱动的治疗方法的设计提供信息， 为患者咨询提供有用的信息，并对患者进行临床试验分层。