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

• 批准号: 7941973
• 负责人: ROBERT L FINDLING
• 金额: $ 23.45万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941973
• 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; 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' s Nodes; Regimen; Regulation; Relative (related person); Research; Research Ethics Committees; Rodent; Rodent Model; Sampling; Schizophrenia; Series; Skin; Source; Staining method; Stains; Stem cells; Structure; Symptoms; System; Techniques; Testing; Thick; Thyroid Hormones; Tissues; Transplantation; Unemployment; Validation; base; brain cell; cell type; 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

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、使人衰弱的精神健康障碍，具有显著的发病率和死亡率。导致精神分裂症的分子和细胞机制仍未明确。尽管精神分裂症一直被认为是一种基于神经递质的疾病，但越来越多的证据表明，少突胶质细胞功能失调是患者精神缺陷的关键因素。目前还没有一种易于处理的系统，可以直接询问精神分裂症患者神经细胞类型的功能特性。目前还不存在能够稳健且可重复分化为特定神经谱系的患者特异性细胞来源。我们建议开发一种基于细胞的系统，通过对患者的神经细胞进行功能分析来探究精神分裂症的分子机制。为了实现这一目标，我们开发了一个尖端的方案，它结合了多学科的技能和专业知识。在Aim 1中，我们将从青少年精神分裂症患者和对照组中获得并表征患者特异性的诱导多能干细胞（iPS）。由于iPS细胞具有多能性，能够分化为人体的所有细胞类型，在Aim 2中，我们将把患者特异性iPS细胞系分化为少突胶质细胞祖细胞（OPCs），为少突胶质细胞提供细胞来源。在该项目的第二阶段，将对这些患者特异性的iPS细胞来源的少突胶质细胞进行表征、比较和功能分析，这些细胞来自对照组和青少年发作的精神分裂症患者，使用体外和体内试验（目标3和目标4分别）。在第二阶段，我们还将积极获取额外的样本，从青少年精神分裂症患者和对照组中提取和表征患者特异性的iPS细胞（目标5）。患者特异性iPS细胞技术有很大的潜力，通过提供基因上独特的、功能性的人类细胞来源，深刻影响我们对人类发育和疾病的理解。通过完成本提案中提出的目标，我们期望提供精神分裂症患者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见解。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、多能性和iPS细胞的优势结合起来，研究导致精神分裂症的细胞和分子功能障碍的新问题。我们期望我们的研究结果将与理解和治疗这种人类疾病直接相关。