Early Onset Parkinson’s disease subtypes and pathogenic mechanisms

早发性帕金森病亚型及致病机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的帕金森病是不同亚型的总称，具有不同的临床特征和不同的症状遗传、炎症和α-突触核蛋白的积累是主要的致病机制。疾病的致病驱动因素，在对患者进行分层的基础上发挥不同的作用。主要致病机制正在成为精准医疗场景的关键。这些致病机制在早发性帕金森病 (EOPD) 中的作用特征是 EOPD 是一种罕见疾病，患者在 50 岁之前就出现 PD，因此会产生影响。我们的中心假设是，EOPD 意味着不同的子类型。预后结果与遗传学、炎症和 α-突触核蛋白的不同贡献相关的患者该提案的总体目标是描述其发病机制中的积累。 EOPD 大型队列中的遗传学、炎症和 α-突触核蛋白积累的影响，并评估这些如何机制可以指导 EOPD 亚型的识别实现这一目标是本次会议的主要目标。该提案将重点关注 1) 描述大量 EOPD 的临床和遗传特征 2) 评估；中央和外周生物样本中存在α-突触核蛋白；3) 分析中央和外周生物样本；与晚发 PD (LOPD) 和未受影响受试者 (CTRL) 相比，EODP 的炎症激活。我们的首要目标是对 EOPD 患者群体进行深入的表型表征，并确定通过无偏见的层次聚类分析对受试者进行基因分析。通过全基因组测序（WGS）来识别已知和新的遗传变异，并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，其中之一。在患有突触核蛋白病的受试者的皮肤活检和脑脊液中发现最有前途的创新生物标志物在第三个目标中，我们将描述单细胞数据和广泛的蛋白质组的表达谱。 EOPD、LOPD 和 CTRL 的外周血和脑脊液炎症标志物面板确定 EOPD 中的炎症激活并表征细胞特异性（先天免疫与适应性免疫）。最后，我们将关联来自三个目标的数据，以评估遗传学、临床、炎症和疾病的概况。 EOPD 亚型的生物标志物数据，而目前该主题的大多数研究都集中在单一方面。该研究提案具有创新性，因为它将不同的疾病机制关联起来以检测该项目的主要意义在于为 EOPD 的发病机制提供新的见解。 EOPD 将为 EOPD 的机制驱动治疗方法的设计提供信息，提供对于患者咨询和对临床试验患者进行分层的有用信息。