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: 9316713
• 负责人: Krishnan Padmanabhan
• 金额: $ 24.38万
• 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/9316713
• 关键词: Action Potentials; Address; Affect; American; Anatomy; Animal Model; Animals; Antipsychotic Agents; Area; Attention; Autopsy; 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; Morphology; Mus; Neurons; Output; Pathologic; 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; Thinness; Transplantation; base; biophysical properties; excitatory neuron; experimental study; 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; 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.

精神分裂症影响着世界上超过 1% 的人口，其中包括 300 万美国人，是一种使人衰弱的疾病 以一系列症状为特征的精神疾病，包括幻觉、妄想、困难 尽管目前有抗精神病药物，但仍会表现出情绪、注意力和记忆力缺陷。 精神分裂症患者的预期寿命比一般人群低 10 年， 容易滥用药物、无家可归，并有自杀的危险。 患有这种疾病的人的生命和公共卫生成本目前还很高。 治疗精神分裂症，以及研究该疾病的病因，包括解剖学和生理学 大脑的破坏一直很困难，因为人们对大脑中细胞的潜在病理学知之甚少。 患者。 为了阐明精神分裂症患者的解剖学和生理学缺陷，本研究 该提案将通过移植重新编程的人类诱导基因来开发一种新的疾病模型 在本次资助的指导部分中，将多能干细胞（iPSC）植入动物系统。 源自精神分裂症患者的神经元中出现的（目标 1）和生理缺陷（目标 2）将被 这两个目标正在进行中，精神分裂症干细胞已成功植入。 此外，还有用于研究小鼠的解剖学和生理学复杂性的新计算方法。 这些细胞是在前两个目标的基础上开发出来的。 该提案的一部分（目标 3）将把个体中发现的解剖学和生理学破坏联系起来。 细胞对患者体内被破坏的神经活动的整体模式进行影响。 拟议的研究有可能为生物学基础提供基本见解 该项目开发的结果和工具将增进对精神分裂症的基本了解。 神经元功能，并可以为筛选新药物疗法检测的高通量检测铺平道路 用于治疗该疾病。