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: 8727110
• 负责人: Krishnan Padmanabhan
• 金额: $ 8.75万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 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 2016-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8727110
• 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 patterning; novel; psychologic; public health relevance; relating to nervous system; research study; response; suicidal risk; tool

DESCRIPTION (provided by applicant): 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 elucidat 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.

描述（由申请人提供）：精神分裂症影响了世界人口的1％以上，包括300万美国人，是一种使人衰弱的精神疾病，其特征是一系列症状，包括幻觉，妄想，难以表达情绪以及注意力和记忆中的缺陷。尽管目前有抗精神病药，但患有精神分裂症的患者的预期寿命比普通人群低10年，容易滥用药物，无家可归，并且有自杀的风险。结果，双方都对患有疾病和公共卫生的人的生活严格严格 成本很大。目前尚无精神分裂症的治愈方法，对疾病的原因进行研究，包括大脑的解剖学和生理破坏，这很困难，因为对患者细胞的潜在病理知之甚少。 为了阐明精神分裂症患者中发现的解剖学和生理缺陷，该提案将通过将重编程的重编程的人诱导多能干细胞（IPSC）移植到动物系统中来开发该疾病的新型模型。在这笔赠款的指导部分中，将表征来自精神分裂症患者的神经元中发生的解剖学（AIM 1）和生理缺陷（AIM 2）。这两个目标都在进行中，精神分裂症干细胞已成功地植入小鼠中。此外，已经开发了用于研究这些细胞的解剖学和生理复杂性的新型计算方法。根据前两个目标中的发现，该提案的独立部分（AIM 3）将将在单个细胞中鉴定出的解剖学和生理破坏与患者中断的神经元活动的全局模式联系起来。 拟议的研究有可能对精神分裂症的生物学基础提供基本见解。该项目中开发的结果和工具将提高对神经元功能的基本理解，并为使用新药物疗法以治疗该疾病的高通量测定法铺平了道路。