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.

帕金森氏病（PD）由其标志性的运动症状定义，包括树，刚性，头肌动症和姿势不稳定是由ni骨多巴胺能逐渐丧失引起的（DA）神经元。公认的帕金森氏病的类别是基于休息树还是基于不在疾病发作。发病时有休息震动的PD患者通常的进展较慢，更好预后比没有休息树的PD患者。我们的初步研究表明控制多巴胺合成，隔离和降解的基因在源自正常受试者的诱导多能干细胞（IPSC）与特发性PD的中脑DA神经元患者。特发性PD患者的某些基因的表达也显着差异有或没有休息树。我们已经开发了一系列新技术 IPSC与A9 DA神经元的区分以及人皮肤成纤维细胞和尿路的直接转换细胞（UTC）至中脑DA神经元。该建议使用这些创新技术，旨在确定可以分离PD患者和正常受试者的分子特征，并区分患有OR的PD患者不在一开始就没有休息树。干细胞技术的融合开发使该项目能够确定特发性帕金森氏病的分子特征，这将大大提高PD诊断，研究和治疗发展。