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Functional Comparison of Induced Pluripotent Stem Cell-Derived Oligodendrocytes i

诱导多能干细胞来源的少突胶质细胞的功能比较 i

基本信息

批准号：
8327085
负责人：
ROBERT L FINDLING
金额：
$ 38.64万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327085
关键词：
Adolescent Adult Affect Aliquot Animal Model Animals Antibodies Applications Grants Astrocytes Axon Biological Assay Biopsy CSPG4 gene Cell Line Cell Proliferation Cell Separation Cell physiology Cells Characteristics Cicatrix Clinical Complex Controlled Study Cues DNA Fingerprinting Data Set Derivation procedure Diagnosis Discipline Disease Ensure Fibroblast Growth Factor 2 Fibroblasts Fingerprint Functional disorder Future Gene Expression Generations Genes Genetic Genomics Goals Growth Factor Homelessness Human Human Development Human body Impaired cognition In Vitro Individual Institutional Review Boards Karyotype Karyotype determination procedure Life Mental disorders Methods Metric Mitogens Molecular Molecular Target Morbidity - disease rate Myelin Nature Nervous System Physiology Neurons Neurotransmitters Oligodendroglia Patients Phase Physiological Platelet-Derived Growth Factor Population Prevalence Process Property Proteome Protocols documentation Psyche structure Ranvier&apos s Nodes Regimen Regulation Relative (related person)Research Rodent Rodent Model Sampling Schizophrenia Series Shivering Skin Source Staining method Stains Stem cells Structure Symptoms System Techniques Testing Thick Thyroid Hormones Tissues Transplantation Unemployment Validation base brain cell cell type cellular targeting cohort comparative disability experience human disease human embryonic stem cell in vivo induced pluripotent stem cell injured insight mortality myelination notch protein novel oligodendrocyte lineage oligodendrocyte precursor pathogen pluripotency prevent progenitor public health relevance relating to nervous system research study response skills social stem stem cell technology suicidal risk transcription factor

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a complex, debilitating mental health disorder associated with significant morbidity and mortality. The molecular- and cellular-based mechanisms that contribute to schizophrenia remain undefined. Although schizophrenia has classically been considered a neurotransmitter-based disorder, there is emerging evidence that dysregulation of oligodendrocyte function is a key contributor to the mental deficits seen in afflicted patients. Currently there is not a tractable system that allows for the direct interrogation of the functional properties of neural cells types from patients with schizophrenia. Patient-specific sources of cells that are capable of robust and reproducible differentiation into specific neural lineages do not exist. We propose to develop a cell-based system whereby neural cells from afflicted individuals can be functionally assayed to interrogate the molecular mechanisms underlying schizophrenia. To achieve this goal we have developed a cutting-edge proposal that that incorporates the skill and expertise of multiple disciplines. In Aim 1 we will derive and characterize patient-specific, induced pluripotent stem (iPS) cells from juvenile-onset schizophrenia patients and controls. Since iPS cells are pluripotent, having the ability to differentiate into all cell types of the human body, in Aim 2 we will differentiate patient-specific iPS cells line into oligodendrocyte progenitor cells (OPCs) to provide a cellular source for oligodendrocytes. In the second phase of this project will characterize, compare, and functionally assay these patient-specific, iPS cell-derived oligodendrocytes from control and juvenile-onset schizophrenia patients using both in vitro and in vivo assays (Aims 3 and 4 respectively). We will also actively procure additional samples to derive and characterize patient-specific, iPS cells from juvenile-onset schizophrenia patients and controls during this second phase (Aim 5). There is great potential for patient-specific iPS cell technology to profoundly impact our understanding of human development and disease by providing genetically distinct, functional sources of human cells. By completing the aims set forth in this proposal we expect to provide a detailed characterization of oligodendrocyte function in patients afflicted with schizophrenia and provide insight into the pathophysiology of this complex disease. We have established an interdisciplinary team that combines strengths in clinical schizophrenia research, neural differentiation and function, as well as pluripotency and iPS cells to interrogate novel questions about the cellular and molecular dysfunction that contributes to schizophrenia. We expect that results from our studies will have immediate relevance to the understanding and treatment of this human disease. PUBLIC HEALTH RELEVANCE: Schizophrenia is a serious psychiatric condition with a worldwide prevalence of approximately 1%. Individuals with schizophrenia experience very severe symptoms and are at an increased risk for suicide, unemployment, permanent disability, and homelessness. Affected adolescents experience even more severe symptoms, tend to be more chronically dysfunctional, suffer from greater cognitive impairments, and may have greater functional and social disability than those with adult-onset schizophrenia. Unfortunately, the cause of schizophrenia is currently unknown. Results of our studies will provide a detailed characterization of brain cell function in patients afflicted with schizophrenia and will offer insight into the mechanisms that contribute to this complex, devastating disease.

描述(由申请人提供)：精神分裂症是一种复杂的、令人衰弱的精神健康疾病，与显著的发病率和死亡率有关。导致精神分裂症的分子和细胞机制仍不清楚。尽管精神分裂症经典地被认为是一种基于神经递质的障碍，但越来越多的证据表明，少突胶质细胞功能调节失调是患者精神缺陷的一个关键因素。目前，还没有一个易于处理的系统来允许直接询问精神分裂症患者神经细胞类型的功能特性。不存在患者特定来源的细胞，这些细胞能够稳健地和可重复地分化为特定的神经谱系。我们建议开发一种基于细胞的系统，通过该系统可以对患有精神分裂症的人的神经细胞进行功能分析，以询问精神分裂症的分子机制。为了实现这一目标，我们开发了一个结合了多个学科的技能和专业知识的尖端提案。在目标1中，我们将从青少年精神分裂症患者和对照中提取和鉴定患者特异性的诱导多能干细胞(IPS)。由于iPS细胞是多能的，具有分化为人体所有细胞类型的能力，在目标2中，我们将把患者特有的iPS细胞系分化为少突胶质前体细胞(OPC)，为少突胶质细胞提供细胞源。在这个项目的第二阶段，将使用体外和体内试验(分别为目标3和4)，对来自对照和青少年精神分裂症患者的患者特有的iPS细胞来源的少突胶质细胞进行特征、比较和功能分析。我们还将积极获取更多的样本，以在第二阶段(目标5)从青少年精神分裂症患者和对照组中提取和鉴定患者特有的iPS细胞。针对患者的iPS细胞技术具有巨大的潜力，通过提供不同基因的、具有功能的人类细胞来源，深刻影响我们对人类发育和疾病的理解。通过完成这项提案中提出的目标，我们希望提供患有精神分裂症患者的少突胶质细胞功能的详细特征，并为这种复杂疾病的病理生理学提供洞察力。我们已经建立了一个跨学科的团队，将临床精神分裂症研究、神经分化和功能以及多能性和iPS细胞的优势结合在一起，询问有关导致精神分裂症的细胞和分子功能障碍的新问题。我们预计，我们的研究结果将与对这种人类疾病的理解和治疗直接相关。公共卫生相关性：精神分裂症是一种严重的精神疾病，全球患病率约为1%。精神分裂症患者的症状非常严重，自杀、失业、永久性残疾和无家可归的风险增加。受影响的青少年症状甚至更严重，往往更慢性功能障碍，遭受更大的认知障碍，并可能有更大的功能和社会残疾比成人精神分裂症。不幸的是，精神分裂症的病因目前尚不清楚。我们的研究结果将提供精神分裂症患者脑细胞功能的详细特征，并将提供对这种复杂、毁灭性疾病的机制的洞察。