ENGRAFTING HUMAN NEURONS INTO ANIMAL MODELS TO STUDY SCHIZOPHRENIA

将人类神经元移植到动物模型中研究精神分裂症

• 批准号: 9233312
• 负责人: Krishnan Padmanabhan
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233312
• 关键词: Action Potentials; Address; Affect; American; Anatomy; Animal Model; Animals; Antipsychotic Agents; Area; Attention; Biological; Biological Models; Brain; Cell physiology; Cells; Cellular Morphology; Complex; Computing Methodologies; Defect; Delusions; Disease; Disease Marker; Disease model; Exhibits; Expressed Emotion; Fire - disasters; Functional disorder; Gene Targeting; General Population; Genes; Genetic; Goals; Grant; Hallucinations; Health Care Costs; High Frequency Oscillation; Homelessness; Human; In Vitro; Individual; Lead; Life Expectancy; Membrane; Memory; Mental disorders; Mentors; Molecular Genetics; Morphology; Mus; Neurons; Output; Pathology; Patients; Pharmacotherapy; Physiological; Physiology; Play; Pluripotent Stem Cells; Population; Property; Public Health; Research; Role; Schizophrenia; Shapes; Stem cells; Structure; Substance abuse problem; Symptoms; System; Testing; The Sun; Transplantation; base; biophysical properties; excitatory neuron; gene function; high throughput screening; inhibitory neuron; insight; nerve stem cell; neural circuit; neuronal circuitry; neuronal patterning; novel; novel therapeutics; psychologic; relating to nervous system; research study; response; suicidal risk; tool

Affecting over 1% of the world’s population, including 3 million Americans, schizophrenia is a debilitating psychiatric disorder characterized by an array of symptoms including hallucinations, delusions, difficulty expressing emotions, and deficits in attention and memory. Despite the currently available antipsychotics, patients suffering schizophrenia have a life expectancy 10 years lower than that of the general population, are prone to substance abuse, homelessness, and are at risk of suicide. As a result, both the toll exacted on the lives of individuals suffering from the disorder and the public health costs are substantial. There is currently no cure for schizophrenia, and research into the causes of the disease, including the anatomical and physiological disruptions in the brain, has been difficult because little is known about the underlying pathology of cells in patients. To elucidate the anatomical and physiological deficits found in the patients with schizophrenia, this proposal will develop a novel model for the disorder by transplanting reprogrammed human inducible pluripotent stem cells (iPSCs) into an animal system. During the mentored portion of this grant, the anatomical (Aim 1) and physiological deficits (Aim 2) that occur in neurons derived from patients with schizophrenia will be characterized. Both aims are underway, and schizophrenia stem cells have been successfully engrafted into mice. Additionally, novel computational methods for studying the anatomical and physiological complexity of these cells have been developed. Based on the discoveries made in the first two aims, the independent portion of this proposal (Aim 3) will relate the anatomical and physiological disruptions identified in individual cells to the global patterns of neuronal activity that are disrupted in patients. The proposed studies have the potential to provide fundamental insights into the biological basis of schizophrenia. The results and tools developed in this project will advance the basic understanding of neuronal function, and could pave the way for high-throughput assays with which to screen new drug therapies for the treatment of the disorder.

影响超过1%的世界人口，包括300万美国人，精神分裂症是一种使人衰弱的疾病。 以一系列症状为特征的精神障碍，包括幻觉、妄想、困难 表达情绪，注意力和记忆力的缺陷。尽管目前有抗精神病药物， 患有精神分裂症的患者的预期寿命比一般人群低10年， 有滥用药物、无家可归和自杀风险的倾向。因此，无论是对收费的 患有这种疾病的个人的生命和公共卫生费用是巨大的。目前没有 治疗精神分裂症，并研究疾病的原因，包括解剖和生理 在大脑中的破坏，一直是困难的，因为很少有人知道细胞的基本病理学， 患者 为了阐明精神分裂症患者的解剖和生理缺陷， 一项提案将通过移植重编程的人类诱导型细胞来开发一种新的疾病模型 多能干细胞（iPSC）进入动物系统。在这一补助金的指导部分，解剖 (Aim 1）和生理缺陷（目的2），发生在神经元来源于精神分裂症患者将是 表征了这两个目标都在进行中，精神分裂症干细胞已经成功地移植到 小鼠此外，新的计算方法，研究解剖和生理的复杂性， 这些细胞已经被开发出来。根据前两个目标的发现，独立的 本提案的一部分（目标3）将涉及在个体中识别的解剖学和生理学破坏， 细胞到患者中被破坏的神经元活动的全局模式。 拟议的研究有可能为以下生物学基础提供基本见解： 精神分裂症本项目的成果和开发的工具将促进对以下问题的基本理解： 神经功能，并可能为高通量检测铺平道路，以筛选新的药物疗法 用于治疗疾病。