in vivo imaging of transplanted human induced-Pluripotent Stem Cell (iPSC) derived neurons to model neurological and psychiatric disorders

对移植的人类诱导多能干细胞 (iPSC) 衍生的神经元进行体内成像，以模拟神经和精神疾病

• 批准号: 9895863
• 负责人: Krishnan Padmanabhan
• 金额: $ 47.76万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895863
• 关键词: Action Potentials; Address; Affect; American; Anatomy; Animals; Antipsychotic Agents; Area; Attention; Autopsy; Brain; Calcium; Cell Differentiation process; Cell physiology; Cells; Code; Cognitive deficits; Complex; Computing Methodologies; Data; Delusions; Development; Disease; Disease Marker; Disease model; Early identification; Expressed Emotion; Fire - disasters; General Population; Goals; Hallucinations; Head; Health Care Costs; Homelessness; Human; Human Activities; Image; In Vitro; Individual; Label; Laser Scanning Microscopy; Life Expectancy; Memory; Mental disorders; Methods; Modeling; Monitor; Morphology; Mus; Neurites; Neurobiology; Neurological Models; Neurons; Pathology; Patients; Pattern; Physiological; Physiology; Pluripotent Stem Cells; Population; Process; Public Health; Research; Schizophrenia; Shapes; Structure; Substance abuse problem; Symptoms; Synapses; System; Technology; Testing; Time; Tissues; Transplantation; Validation; Work; area striata; awake; base; calcium indicator; gray matter; human disease; imaging modality; in vivo; in vivo calcium imaging; in vivo imaging; induced pluripotent stem cell; insight; nerve stem cell; nervous system disorder; neural circuit; neuropsychiatric disorder; novel; patient population; relating to nervous system; stem cells; suicidal risk; tool; two-photon

Project Summary 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 induced- Pluripotent Stem Cells (iPSCs) into an animal system and imaging the structure and function of these cells in vivo. In Aim 1, this project will develop the technologies needed to perform structural characteriation of human iPSC-derived neurons including developing methods to analyze neural circuit structure and anatomical dynamics. In Aim 2, this project will develop technologies needed to image the population calcium activity of human iPSC-derived neurons in vivo and develop new analysis methods for studying and characterizing this acitivity. In Aim 3, this project will apply these technologies to characterize the structure and spontaneous activity patterns of human iPSC-derived neurons in vivo. Taken together, this work will develop a powerful new platform for dissecting the structure and function of human neural circuits with the aims of understanding the neurobiological basis of schizophrenia.

项目摘要 精神分裂症影响世界人口的1%以上，包括300万美国人，是一种 以包括幻觉在内的一系列症状为特征的衰弱性精神障碍， 妄想症，表达情感困难，注意力和记忆力缺陷。尽管 目前可用的抗精神病药物，患有精神分裂症的患者的预期寿命为10 年龄低于一般人口，容易滥用药物，无家可归， 有自杀的危险因此，无论是对遭受痛苦的个人的生命造成的损失， 公共卫生成本是巨大的。目前还没有治愈 精神分裂症，并研究疾病的原因，包括解剖和 大脑中的生理干扰，一直很困难，因为很少有人知道， 患者细胞的潜在病理学。 为了阐明在患者中发现的解剖和生理缺陷， 精神分裂症，这项建议将开发一种新的模型， 将人诱导多能干细胞（iPSC）重编程到动物系统中， 在体内对这些细胞的结构和功能进行成像。在目标1中，本项目将开发 对人类iPSC衍生神经元进行结构表征所需的技术 包括开发分析神经回路结构和解剖动力学的方法。在 目标2，该项目将开发成像所需的技术， 人iPSC衍生的神经元，并开发新的分析方法， 这一活动的特点。在目标3中，该项目将应用这些技术来表征 体内人iPSC衍生神经元的结构和自发活动模式。采取 总之，这项工作将开发一个强大的新平台，解剖的结构和功能， 人类神经回路的目的是了解的神经生物学基础， 精神分裂症