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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：
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.

总结多巴胺能神经元的丢失是帕金森病（PD）的主要细胞病理学基础。一一个基本但尚未解决的挑战是如何补充多巴胺能神经元，多巴胺调节的神经回路。多巴胺能神经元纹状体内移植可以逆转PD的行为缺陷，突出了纹状体多巴胺的治疗价值。但移植的干细胞的功效受到诱导神经元的存活和整合的限制，肿瘤发生的可能性。该提案的长期目标是确定一个新的再生战略，使用患者特异性内源性神经胶质细胞的神经元诱导。我们的初步结果显示，可以在成年纹状体中体内重编程为成神经细胞。这些神经母细胞增殖并产生成熟的神经元，当供应有神经营养因子或小化合物丙戊酸时。最重要的是，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。三在本申请中提出了进一步分析和优化体内重编程过程的目的：1）优化多巴胺能神经元产生的重编程过程，2）功能上表征这些诱导的多巴胺能神经元在成人大脑中，和3）检查的可翻译性诱导多巴胺能神经元。这项工作的结果可能会导致一个全新的治疗模式，警局