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Induced Adult Neurogenesis for Parkinson's Disease

帕金森病的诱导成人神经发生

基本信息

批准号：
9751421
负责人：
Chun-Li Zhang
金额：
$ 47.71万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751421
关键词：
Adopted Adult Animal Model Animals Astrocytes Behavioral Biological Brain CNS degeneration Caregivers Cell Transplantation Cell Transplants Cells Cellular biology Chemicals Clinical Communication Corpus striatum structure Data Disease Dopamine Elderly Electrophysiology (science)Emotional Failure Foundations Gene Expression Generations Goals Histocompatibility Human Immunohistochemistry In Vitro Laboratories Lead Mediating Mus Nature Neuraxis Neuroglia Neurons Neurotransmitters Outcome Parkinson Disease Pathologic Patients Pharmacology Phenotype Pluripotent Stem Cells Population Process Production Proliferating Protocols documentation Publishing Rabies virus Reporting Research Safety Specific qualifier value Spinal Cord Stem cell transplant Stem cells Substantia nigra structure Therapeutic Translating Transplantation Traumatic Brain Injury Undifferentiated Valproic Acid Work adult neurogenesis age effect aged base cellular pathology dopaminergic differentiation dopaminergic neuron fetal improved in vivo motor deficit mouse model neural circuit neuroblast neuron loss neuronal circuitry neurotrophic factor novel novel strategies novel therapeutics pars compacta progenitor regenerative repaired transcription factor tumorigenesis

项目摘要

SUMMARY Loss of dopaminergic neurons is the principal cellular pathology underlying Parkinson's disease (PD). A fundamental but unresolved challenge is how to replenish dopaminergic neurons and restore the neurotransmitter dopamine-regulated neural circuits. Transplantation of dopaminergic neurons into the striatum can reverse behavioral deficits of PD, highlighting the therapeutic value of striatal dopamine. However, the efficacy of transplanted stem cells is limited by the survival and integration of induced neurons, as well as, the potential for tumorigenesis. The long-term goal of this proposal is to define a new regenerative strategy for neuronal induction using patient-specific endogenous glial cells. Our preliminary results show that resident glia can be in vivo reprogrammed into neuroblasts in the adult striatum. These neuroblasts proliferate and generate mature neurons when supplied with neurotrophic factors or the small chemical compounds valproic acid. Most importantly, the newly generated striatal neurons can functionally integrate into local neuronal circuits. Three aims are proposed in this application to further analyze and optimize the in vivo reprogramming process: 1) to optimize the reprogramming process for the generation of dopaminergic neurons, 2) to functionally characterize these induced dopaminergic neurons in the adult brain, and 3) to examine translatability of induced dopaminergic neurons. The results of this work may lead to an entirely novel treatment paradigm for PD.

摘要多巴胺能神经元的缺失是帕金森病(PD)的主要细胞病理基础。一个根本但尚未解决的挑战是如何补充多巴胺能神经元并恢复神经递质受多巴胺调节的神经回路。纹状体内多巴胺能神经元的移植能逆转帕金森病患者的行为缺陷，凸显纹状体多巴胺的治疗价值。然而，干细胞移植的有效性受到诱导神经元的存活和整合的限制，以及肿瘤发生的可能性。这项提议的长期目标是定义一个新的再生战略使用患者特有的内源性神经胶质细胞进行神经元诱导。我们的初步结果显示，常驻神经胶质细胞可以在体内重新编程为成年纹状体的神经母细胞。这些神经母细胞增殖并生成当供应神经营养因子或丙戊酸的小化合物时，成熟的神经元。多数重要的是，新产生的纹状体神经元可以在功能上整合到局部神经元回路中。三本申请的目的是进一步分析和优化体内重编程过程：1) 优化产生多巴胺能神经元的重编程过程，2)在功能上描述这些诱导的成人大脑中的多巴胺能神经元，以及3)检查诱导的多巴胺能神经元。这项工作的结果可能导致一种全新的治疗模式警察。