Neuron and Glial Cellular Signatures from Normal and Diseased iPS Cells

正常和患病 iPS 细胞的神经元和神经胶质细胞特征

• 批准号: 9352935
• 负责人: STEVEN M FINKBEINER
• 金额: $ 0.85万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352935
• 关键词: Address; Affect; Astrocytes; Behavior; Bioinformatics; Biological; Biological Assay; Cells; Cellular biology; Code; Collaborations; Communities; Community Outreach; Complex; Computational Biology; Data; Data Provenance; Data Set; Databases; Disease; Disease Progression; Disease model; Environment; Exhibits; Familial Amyotrophic Lateral Sclerosis; Fostering; Foundations; Genes; Genetic; Genome; Goals; Health; Human; Huntington Disease; Information Resources; Inherited; Knowledge; Lead; Learning; Libraries; Machine Learning; Malignant Neoplasms; Molecular; Molecular Profiling; Molecular Target; Motor Neuron Disease; Network-based; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Online Systems; Parkinson Disease; Pathway interactions; Patients; Persons; Physiology; Predictive Value; Process; Proteomics; Resources; Scientist; Scourge; Signal Transduction Pathway; Site; Software Tools; Spinal Muscular Atrophy; Structure; Symptoms; Technology; Textbooks; Time; Variant; base; brain cell; cancer cell; cell type; disease-causing mutation; epigenomics; genome sequencing; induced pluripotent stem cell; innovation; insight; loss of function; member; metabolomics; molecular phenotype; novel therapeutics; outreach program; predictive modeling; receptor; response; single cell analysis; statistics; stem cell technology; tool; transcriptomics; whole genome

DESCRIPTION (provided by applicant): There is a critical need to define the state and predict the behavior of human brain cells in health and disease. The number of different cell types in the CNS remains undefined, and despite a demographically ordained wave of neurodegenerative diseases, not a single disease-modifying therapy exists. Our knowledge of the CNS and the foundation for intervening rationally in disease would be dramatically advanced by generating quantitative molecular phenotypes essentially cell signatures of human neurons, astrocytes and oligodendrocytes from healthy people and from patients with motor neuron disease, Huntington's disease, and Parkinson's disease. The CNS is so unique that studying non-neuronal cells does not provide much assistance. Despite this desperate need, the inaccessibility of human brain cells meant studying them would have been impossible until the recent discovery of cellular reprogramming and induced pluripotent stem cell technology. Here we propose to form the NeuroLINCS consortium to accomplish these goals. We have handpicked the team to bring in critical expertise in iPSC technology, disease modeling, transcriptomics, epigenomics, metabolomics, whole genome sequencing, proteomics, high content, high throughput longitudinal single cell analysis, other cell-based assays, bioinformatics, statistics and computational biology. In addition, we are collaborating with Google to bring in special expertise in machine learning and the integration of signatures across platforms into highly predictive models of responses to perturbagens. Together, we expect to develop cell signatures of an array of human brain cell types under different conditions that should be broadly applicable to the LINCs community. We also anticipate generating innovative software tools and approaches that will make the signature generating process cheaper, faster, and more reliable. Besides the unique combination of expertise represented within NeuroLINCS, another distinguishing feature is the long track record that its members have of collaborating with each other. That collaborative spirit will be expressed in NeuroLINCS through its significant and multifaceted community outreach programs. These will involve specific and detailed plans to make the data and tools that NeuroLINCS generates available to the community, to interact with other LINCS sites, and to prepare for DCIC and the prospect of disseminating knowledge and resources at scale.

描述（由申请人提供）：迫切需要定义健康和疾病中人脑细胞的状态并预测其行为。CNS中不同细胞类型的数量仍然不确定，尽管神经退行性疾病的人口统计学规定的浪潮，但不存在单一的疾病修饰疗法。通过从健康人和运动神经元疾病、亨廷顿舞蹈病和帕金森病患者中生成定量分子表型（本质上是人类神经元、星形胶质细胞和少突胶质细胞的细胞特征），我们对中枢神经系统的了解和合理干预疾病的基础将大大提高。中枢神经系统是如此独特，研究非神经元细胞并没有提供太多的帮助。尽管有这种迫切的需求，但人类脑细胞的不可及性意味着在最近发现细胞重编程和诱导多能干细胞技术之前，研究它们是不可能的。 在这里，我们建议成立NeuroLINCS联盟来实现这些目标。我们精心挑选的团队带来了iPSC技术，疾病建模，转录组学，表观基因组学，代谢组学，全基因组测序，蛋白质组学，高含量，高通量纵向单细胞分析，其他基于细胞的测定，生物信息学，统计学和计算生物学的关键专业知识。此外，我们正在与谷歌合作，引入机器学习方面的特殊专业知识，并将跨平台的签名集成到对扰动的高度预测性响应模型中。我们希望在不同的条件下开发一系列人脑细胞类型的细胞特征，这些细胞特征应该广泛适用于LINCs社区。我们还期望产生创新的软件工具和方法，使签名生成过程更便宜，更快，更可靠。 除了NeuroLINCS内所代表的专业知识的独特组合外，另一个显着特征是其成员相互合作的长期记录。这种合作精神将通过其重要和多方面的社区外展计划在NeuroLINCS中表达。这将涉及具体和详细的计划，使数据和工具，NeuroLINCS产生提供给社区，与其他LINCS网站互动，并准备DCIC和前景的传播知识和资源的规模。