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Generation and integration of new CNS neurons by in vivo directed conversion

通过体内定向转换产生和整合新的中枢神经系统神经元

基本信息

批准号：
8703828
负责人：
Asa Abeliovich
金额：
$ 59.64万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703828
关键词：
Address Adult Architecture Astrocytes Autologous Behavioral Brain Brain region Cell Culture Techniques Cell Transplantation Cells Cerebral cortex Dopamine Evaluation Gene Expression Profiling Generations Genes Genetic Transcription Glutamates Goals In Situ In Vitro Lead Lentivirus Vector Light Maps Membrane Midbrain structure Molecular Mus Neurons Neurotransmitters Pattern Phenotype Physiological Plastics Property Prosencephalon Regenerative Medicine Regulation Relative (related person)Reporting Rodent Slice Source Stem cells Synapses Technology Therapeutic Time Toxic effect Transgenic Mice Transplantation Validation Viral Vector biophysical properties cell type cellular transduction embryonic stem cell in vivo inhibitory neuron interest neurochemistry neuronal circuitry novel optical imaging optogenetics patch clamp vector vector control

项目摘要

DESCRIPTION (provided by applicant): The goal of this application is to investigate the feasibility and requirements of converting existing in vivo, differentiated cells of the adult CNS - such as astroglia - into functional and appropriately integrated neurons, using in situ directed neuronal conversion (IDNC). IDNC is novel and distinct from stem cell approaches. With IDNC, a cocktail of transcription regulators is transduced into mature CNS cells, such as astroglia, using polycistronic lentiviral vectors or otherwise. These factors lead to a rapid and directed conversion into a distinct mature neuronal phenotype. Such directed conversion challenges the basic tenet that differentiated cell phenotypes are inherently stable - particularly in situ in the CNS. Directed conversion potentially overcomes some of the inherent difficulties with other therapeutic cell replacement strategies, such as stem cell approaches. Directly converting existing cells may be least intrusive on the general architecture of existing circuitry. A second and perhaps greater challenge is the functional integration of newly converted neurons into CNS local circuitry. This problem will be address using a variety of physiological and optical imaging approaches.

描述（由申请人提供）：本申请的目的是研究使用原位定向神经元转换（IDNC）将成人中枢神经系统现有的体内分化细胞（例如星形胶质细胞）转化为功能性和适当整合的神经元的可行性和要求。 IDNC 是一种新颖且不同于干细胞方法的方法。通过 IDNC，使用多顺反子慢病毒载体或其他方式将转录调节因子混合物转导到成熟的 CNS 细胞中，例如星形胶质细胞。这些因素导致快速、定向转化为独特的成熟神经元表型。这种定向转化挑战了分化细胞表型本质上稳定的基本原则——特别是在原位中枢神经系统。定向转化可能克服其他治疗性细胞替代策略（例如干细胞方法）的一些固有困难。直接转换现有单元可能对现有电路的一般架构的干扰最小。第二个也许更大的挑战是将新转换的神经元功能整合到中枢神经系统局部电路中。这个问题将通过各种生理和光学成像方法来解决。