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：
9176194
负责人：
Chun-Li Zhang
金额：
$ 47.7万
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/9176194
关键词：
Adopted Adult Animal Model Animals Astrocytes Behavioral Biological Brain CNS degeneration Caregivers 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 Patients Phenotype Pluripotent Stem Cells Population Process Production Proliferating Protocols documentation Publishing Rabies virus 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 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.

概括多巴胺能神经元的丧失是帕金森氏病（PD）的主要细胞病理学。一个基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多巴胺调节的神经回路。将多巴胺能神经元移植到纹状体中可以逆转PD的行为缺陷，突出纹状体多巴胺的治疗价值。但是，移植干细胞的功效受诱导的神经元的存活和整合的限制，以及肿瘤发生的潜力。该提议的长期目标是定义一种新的再生策略使用患者特异性内源性神经胶质细胞的神经元诱导。我们的初步结果表明居民神经胶质可以在成年纹状体中的体内重编程为神经细胞。这些神经细胞扩散并产生成熟的神经元在供应神经营养因子或小型化合物丙戊酸时。最多重要的是，新生成的纹状体神经元可以在功能上集成到局部神经元电路中。三在本应用中提出了目标，以进一步分析和优化体内重编程过程：1）优化生成多巴胺能神经元的重编程过程，2）表征成人大脑中这些诱导的多巴胺能神经元，3）检查诱导多巴胺能神经元。这项工作的结果可能会导致完全新颖的治疗范式 PD。