Molecular Segregation of Parkinson’s Disease by Patient-Derived Neurons

患者来源的神经元对帕金森病的分子分离

基本信息

批准号：
10613419
负责人：
JIAN FENG
金额：
$ 44.9万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613419
关键词：
Address Age Back Biological Markers Bradykinesia Categories Cells Clinical Clinical Trials Design Complex Development Diagnosis Diagnostic Disease Dopamine Fibroblasts Gene Expression Gene Expression Profile Genes Genetic Goals Human Idiopathic Parkinson Disease Induced pluripotent stem cell derived neurons Laboratories Methods Midbrain structure Molecular Molecular Profiling Neuronal Differentiation Neurons Onset of illness Oxidative Stress Parkinson Disease Patients Physiology Preparation Prognosis Property Research Rest Tremor Sampling Series Shapes Skin Stem Cell Development Symptoms Testing Tissue-Specific Gene Expression Tremor Urinary tract biomarker development cohort disease diagnosis disorder subtype dopaminergic neuron endophenotype improved induced pluripotent stem cell innovation innovative technologies insight new technology novel posture instability predictive marker research and development segregation sex stem stem cell technology therapeutic development urinary

项目摘要

Parkinson’s disease (PD) is defined by its hallmark locomotor symptoms including tremor, rigidity, bradykinesia and postural instability, which are caused by a progressive loss of nigral dopaminergic (DA) neurons. A well-recognized categorization of Parkinson’s disease is based on whether rest tremor is present or not at disease onset. PD patients who have rest tremor at onset generally have slower progression and better prognosis than PD patients without rest tremor at onset. Our preliminary study showed that the expression of genes controlling dopamine synthesis, sequestration and degradation was significantly different between midbrain DA neurons derived from induced pluripotent stem cells (iPSC) of normal subjects vs. idiopathic PD patients. Expression of some of these genes was also significantly different between idiopathic PD patients with or without rest tremor at onset. We have developed a series of new technologies including the differentiation of iPSCs to A9 DA neurons and the direct conversion of human skin fibroblasts and urinary track cells (UTCs) to midbrain DA neurons. Using these innovative technologies, the proposal aims to identify molecular signatures that can segregate PD patients and normal subjects, and distinguish PD patients with or without rest tremor at onset. The converging development of stem cell technologies enables this project to identify molecular signatures of idiopathic Parkinson’s disease, which will significantly advance PD diagnosis, research and therapeutic development.

帕金森病 (PD) 的定义是其标志性运动症状，包括震颤、强直、运动迟缓和姿势不稳定，由黑质多巴胺能 (DA) 逐渐丧失引起帕金森病的公认分类是基于是否存在静止性震颤。发病时有静止性震颤的 PD 患者通常病情进展较慢且病情较好。我们的初步研究表明，PD患者的预后优于发作时无静止性震颤的患者。控制多巴胺合成、隔离和降解的基因在不同个体之间存在显着差异。正常受试者诱导多能干细胞 (iPSC) 衍生的中脑 DA 神经元与特发性 PD 其中一些基因的表达在特发性帕金森病患者之间也存在显着差异。我们开发了一系列新技术，包括发作时有或没有静止性震颤。 iPSC 分化为 A9 DA 神经元以及人皮肤成纤维细胞和泌尿道的直接转化该提案旨在利用这些创新技术来识别中脑 DA 神经元。分子特征可以区分帕金森病患者和正常受试者，并区分帕金森病患者或干细胞技术的融合发展使该项目能够在发作时无静止性震颤。识别特发性帕金森病的分子特征，这将显着推进帕金森病的诊断，研究和治疗开发。