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）：精神分裂症影响着世界上超过 1% 的人口，包括 300 万美国人，它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力缺陷。尽管目前有抗精神病药物，但精神分裂症患者的预期寿命比普通人群低 10 年，并且容易滥用药物、无家可归，并且有自杀的风险。结果，对患有这种疾病的个人的生命和公共卫生造成了损失 成本是巨大的。目前，精神分裂症还无法治愈，而且对该疾病的病因（包括大脑的解剖学和生理学破坏）的研究也很困难，因为对患者细胞的潜在病理学知之甚少。 为了阐明精神分裂症患者的解剖学和生理学缺陷，该提案将通过将重新编程的人类诱导多能干细胞（iPSC）移植到动物系统中来开发一种新的疾病模型。在本次资助的指导部分中，将对来自精神分裂症患者的神经元中发生的解剖学（目标 1）和生理学缺陷（目标 2）进行表征。这两个目标都在进行中，精神分裂症干细胞已成功移植到小鼠体内。此外，还开发了用于研究这些细胞的解剖和生理复杂性的新计算方法。基于前两个目标的发现，该提案的独立部分（目标 3）将把单个细胞中发现的解剖学和生理学破坏与患者中被破坏的神经元活动的整体模式联系起来。 拟议的研究有可能为精神分裂症的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神经元功能的基本了解，并可能为筛选治疗该疾病的新药物疗法的高通量测定铺平道路。