Correcting Cognitive Deficits by Gene Therapy

通过基因疗法纠正认知缺陷

• 批准号: 7646208
• 负责人: GUORONG ZHANG
• 金额: $ 12.31万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7646208
• 关键词: 2 year old; Age; Aging; Agriculture; Area; Auditory; Brain; Calpain; China; Chinese People; Cognitive deficits; Cytoplasmic Granules; Discrimination; Discrimination Learning; Doctor of Medicine; Doctor of Philosophy; Faculty; Gene Expression; Genetic; Glutamates; Goals; HSV-1 vector; Helper Viruses; Hippocampus (Brain); Hospitals; Intervention; Knowledge; Laboratories; Learning; Length; Long-Term Potentiation; Maintenance; Measures; Mediating; Memory; Molecular Biology; Monkeys; N-Methyl-D-Aspartate Receptors; Neuroanatomy; Neurodegenerative Disorders; Neurons; Neurosciences; Pathway interactions; Phosphorylation; Physiology; Positioning Attribute; Protein Kinase C; Protein Kinase C Activation Pathway; Rattus; Recombinant Proteins; Regulation; Reporting; Research; Research Project Grants; Residencies; Reversal Learning; Rodent; Scientist; Signal Pathway; Simplexvirus; Specific qualifier value; Stroke; Support System; Synapses; System; Tetracycline Control; Tetracyclines; Time; Training; Transgenic Mice; United States National Institutes of Health; Universities; Viral Vector; Visual; Work; aged; auditory discrimination; career; effective therapy; gene therapy; instructor; neurosurgery; overexpression; programs; promoter; research study; theories; vector; virology; visual learning; young adult

DESCRIPTION (provided by applicant): I, Dr. Guo-rong Zhang, have had a remarkable journey. I am from a small agricultural town about a day's drive south of Beijing, China. I worked my way up through the Chinese system, first at a provincial University and then in Beijing, obtaining both the M.D. and Ph.D. I then joined Dr. Geller's Laboratory at the W. Roxbury VA Hospital/Harvard Med. Schl. In July 2004, I was promoted to Instructor, a faculty level position. In Feb. 2004,1 received permanent residency status. I am intent on having an academic career in the US. I am skilled in neurosurgery and neuroanatomy, and have a broad overall knowledge of neuroscience. This proposal will provide training in molecular biology, virology, neuronal physiology, and learning and memory. Training includes coursework and a research program, emphasizing the new areas for me. This training should enable me to become an independent scientist and obtain NIH research grant (R01) support. Cognitive deficits are caused by aging, specific neurodegenerative diseases, stroke, and other conditions. No effective treatments are available. Gene therapy has tremendous potential for treating specific cognitive deficits. Learning theories hypothesize that neurons in a specific circuit use specific signaling pathways to modify synaptic strengths, thereby mediating learning. Thus, altering the physiology of a small group of neurons can potentiate a specific circuit and enhance learning, providing a treatment for cognitive deficits. I have established that genetic activation of protein kinase C (PKC) pathways in small groups of rat postrhinal cortex neurons enhances learning of visual object discriminations. PKC pathways were activated in several hundred predominantly glutamatergic and GABAergic neurons (using a Herpes Simplex Virus (HSV-1) vector that expresses a constitutively active PKC). Also, I showed that activating PKC pathways in small groups of hippocampal dentate granule neurons enhances learning of an auditory reversal discrimination, and, in aged rats, corrects deficits in a spatial learning. The long-term goal of this proposal is to develop a gene therapy treatment for cognitive deficits. The first specific aim will characterize correction of cognitive deficits in aged rats following activation of PKC pathways in small groups of hippocampal or postrhinal cortex neurons. The second specific aim will determine how long the recombinant PKC must be expressed to correct the learning deficits.

描述（由申请人提供）： 我，张国荣博士，经历了一段非凡的旅程。我来自中国北京以南大约一天车程的一个农业小镇。我在中国的体系中一路向上，先是在一所省立大学，然后在北京，获得了医学博士和博士学位。然后我加入了盖勒博士位于 W. Roxbury VA 医院/哈佛医学院的实验室。施尔。 2004年7月，我晋升为讲师，属于教职级别的职位。 2004年2月，1获得永久居留身份。我一心想在美国从事学术事业。我精通神经外科和神经解剖学，并对神经科学有广泛的整体了解。该提案将提供分子生物学、病毒学、神经生理学以及学习和记忆方面的培训。培训包括课程作业和研究计划，强调我的新领域。这次培训应该使我能够成为一名独立科学家并获得 NIH 研究拨款 (R01) 支持。认知缺陷是由衰老、特定神经退行性疾病、中风和其他疾病引起的。没有有效的治疗方法。基因疗法在治疗特定认知缺陷方面具有巨大潜力。学习理论假设特定回路中的神经元使用特定的信号通路来改变突触强度，从而调节学习。因此，改变一小群神经元的生理机能可以增强特定的回路并增强学习能力，从而治疗认知缺陷。我已经确定，小群大鼠鼻后皮层神经元中蛋白激酶 C (PKC) 通路的基因激活可以增强视觉对象辨别的学习能力。 PKC 通路在数百个主要谷氨酸能和 GABA 能神经元中被激活（使用表达组成型活性 PKC 的单纯疱疹病毒 (HSV-1) 载体）。此外，我还发现，激活一小群海马齿状颗粒神经元中的 PKC 通路可以增强听觉反转辨别的学习，并且在老年大鼠中可以纠正空间学习的缺陷。该提案的长期目标是开发一种治疗认知缺陷的基因疗法。第一个具体目标是在小群海马或鼻后皮层神经元中激活 PKC 通路后纠正老年大鼠的认知缺陷。第二个具体目标将确定重组 PKC 必须表达多长时间才能纠正学习缺陷。