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.

精神分裂症影响了全球超过1％的人口，包括300万美国人，令人衰弱 精神疾病的特征是一系列症状，包括幻觉，妄想，困难 表达情绪，并在注意力和记忆中定义。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，是 容易滥用毒品，无家可归，并且有自杀的风险。结果，双收费都在 患有这种疾病的人的生活和公共卫生成本是巨大的。目前没有 治愈精神分裂症，并研究该疾病的原因，包括解剖学和生理 大脑中的破坏很困难，因为对细胞中的基本病理知之甚少 患者。 为了阐明精神分裂症患者中发现的解剖学和身体缺陷， 提案将通过移植重编程的人诱导来开发一种疾病的新型模型 多能干细胞（IPSC）进入动物系统。在这笔赠款的修补部分期间，解剖学 （AIM 1）和从精神分裂症患者衍生的神经元中发生的身体缺陷（AIM 2）将是 特征。这两个目的都在进行中，精神分裂症干细胞已成功地植入 老鼠。此外，用于研究的新计算方法用于研究的解剖学和物理复杂性 这些细胞已经开发。基于前两个目标中的发现，独立 该提案的一部分（AIM 3）将关联个体中确定的解剖和身体破坏 细胞到患者中断的神经元活性的全球模式。 拟议的研究有可能提供对生物学基础的基本见解 精神分裂症。该项目中开发的结果和工具将提高对 神经元功能，可以为筛查新药物疗法的高通量测定法铺平道路 用于治疗疾病。