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; 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.

抽象的 帕金森氏病是具有不同亚型的雨伞，具有不同的临床特征和不同的特征 潜在的致病机制。 α-突触核蛋白的遗传学，感染和积累是主要的 该疾病的致病驱动因素，在患者亚组中起不同的作用。根据 在精密医学的情况下，主要的致病机制已成为关键。广泛的 这些致病机制在早期发作帕金森氏病（EOPD）中的作用的表征是 缺乏。 EOPD是一种罕见的疾病，PD在50岁之前表现出患者，从而影响 这些主题的大部分生活。我们的中心假设是EOPD意味着不同的子类型 与遗传学，感染和α-突触核蛋白的多种贡献有关的预后结果患者 在其发病机理中积累。该提案的总体目标是表征贡献 大量EOPD中的遗传学，感染和α-突触核蛋白的积累和评估如何 机制可以指导EOPD子类型的识别。为了实现这一目标的主要目的 提案将重点放在1）表征大量EOPD队列的临床和遗传特征； 2）评估 中央和周围生物样本中α-核蛋白的存在； 3）分析中央和外围 EODP的炎症激活与晚期发作PD（LOPD）和非影响受试者（CTRL）相比。为了 首先，我们将对EOPD患者人群进行深层表型表征，并确定 表型簇通过公正的分层群集分析。受试者也将普遍介绍 通过整个基因组测序（WGS），以鉴定已知和新的遗传变异体以及用于鉴定 稀有基因变体的负担分析。在第二个目标中，我们将评估α-突触核蛋白扩增测定法，一个 在皮肤活检和脑脊液中，最有希望的创新生物标志物是 eopd。在第三个目标中，我们将表征单细胞数据的表达曲线和广泛的蛋白质组学 来自EOPD，LOPD和CTRL的外周血和脑脊液的炎症标记的面板 确定EOPD中的炎症激活并表征细胞特异性（先天性与适应性免疫组织化学）。 最后，我们将将三个目的的数据关联，以评估遗传学，临床，炎症和 EOPD子类型中的生物标志物数据。虽然当前有关该主题的大多数研究都集中在单一方面 关于该疾病，该研究提案具有创新性，因为它与检测到不同的疾病机制相关 EOPD的子类型。该项目的主要意义将是提供有关的新见解。 EOPD将为EOPD的机构驱动的治疗方法设计提供信息，提供 用于患者咨询的有用信息，并对患者进行临床试验进行分层。