Cellular and molecular mechanisms of brain dysfunction in NF1

NF1脑功能障碍的细胞和分子机制

• 批准号: 10347337
• 负责人: Nan Yang
• 金额: $ 39.83万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347337
• 关键词: Affect; Alleles; Animal Model; Architecture; Behavioral; Biological Assay; Biological Models; Biological Process; Brain; Brain Diseases; Cell Differentiation process; Cell Line; Cell Proliferation; Cell division; Cell model; Cell physiology; Cells; Clinic; Clinical; Clinical Trials; Cognitive deficits; Complex; Cytokinesis; Data; Defect; Deformity; Development; Disease; Disease model; Electrodes; Electrophysiology (science); Epigenetic Process; Evolution; First Pregnancy Trimester; Fostering; Functional disorder; Gene Expression Profiling; Genetic Engineering; Goals; High Prevalence; Human; Imaging Device; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Laboratories; Lead; Light; Macrocephaly; Measurement; Mission; Mitotic; Modeling; Molecular; Morphology; Mus; Mutation; NF1 gene; NF1 mutation; National Institute of Neurological Disorders and Stroke; Neurobehavioral Manifestations; Neurodevelopmental Disorder; Neuroepithelial; Neuroepithelial Cells; Neurofibromatoses; Neurofibromatosis 1; Neuroglia; Neurologic; Neuronal Differentiation; Neurons; Organoids; Output; Pathogenesis; Pathogenicity; Patients; Phenotype; Pilot Projects; Property; Proteins; Publishing; Radial; Research; Rodent; Role; Screening procedure; Signal Pathway; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Transgenic Organisms; Translations; Ventricular; Work; autism spectrum disorder; base; brain dysfunction; cell behavior; cell type; disorder prevention; excitatory neuron; gamma-Aminobutyric Acid; gene regulatory network; human model; improved; induced pluripotent stem cell; inhibitory neuron; insight; interdisciplinary approach; loss of function mutation; migration; mouse model; mutant; nerve stem cell; nervous system disorder; neurodevelopment; novel; novel therapeutic intervention; novel therapeutics; progenitor; relating to nervous system; species difference; stem cell biology; stem cells; tool; transcriptome; treatment strategy

Despite the well-recognized cognitive deficits in Neurofibromatosis type 1 (NF1), the mechanisms underlying the neuropathophysiology remain unclear. The clear lack of translation from findings in mouse models to the clinic manifests the inherent species differences in the development, architecture and function of rodent and human brains, and underscores the urgent need to develop and use human model systems to study aspects of human brain disorders and to bridge the translational gap to the clinic. Our long-term goal is to develop and use human cellular models to elucidate the molecular and cellular mechanisms underlying the cognitive deficits associated with NF1. Recent advances in the field of epigenetic reprogramming, stem cell biology and genetic engineering has rendered us a unique opportunity to model neurodevelopmental disorders such as NF1 in a manner that is highly complementary to murine transgenic approaches by that maintains fidelity with complex human cellular contexts. The objective of the current study is to harness such tools to characterize the abnormalities in neurodevelopment and neuronal network activity caused by NF1-associated mutations and determine the cellular and molecular mechanisms underlying Neurofibromin 1 (NF1 encoding protein) - regulated biological processes in different cellular contexts. Based on the preliminary data produced in the applicant’s laboratory, we hypothesize that disease associated mutations in NF1 affect proliferation and cell fate commitment of human neural progenitor cells that control neuronal output; and impair neuronal network activity through a potentially human-specific mechanism. The hypothesis will be tested using two complementary cellular models: 1) human brain organoids will be used to investigate the role of Neurofibromin 1 in human neural progenitor cell types, especially the outer radial glial cells that are largely absent in the rodent developing cortices. A multidisciplinary approach will be used to characterize cell type-specific defects in neuroepithelial cell expansion, migration, differentiation, and the mitotic properties of cells; 2) induced neuronal (iN) system, which was developed by the applicant and others, will be used to dissect the cellular mechanisms underlying the irregular neuronal network activity observed in cultures consisting of NF1 mutant neurons. The current study would be the first systematic investigation of Neurofibromin 1 completion of the proposed project function in the neural system using a human model system. Successful will provide novel knowledge on the role of Neurofibromin 1 in different neural cell types that are relevant to the pathophysiology of NF1. Given the high prevalence of Autism in NF1, the proposed research also has the potential to shed light on the key molecular and cellular mechanisms underlying idiopathic Autism.

尽管1型神经纤维瘤病（NF 1）存在公认的认知缺陷， 神经病理生理学仍不清楚。明显缺乏从小鼠模型中的发现到临床的转化 显示了啮齿动物和人类在发育、结构和功能上的固有种属差异 大脑，并强调迫切需要开发和使用人类模型系统来研究人类的各个方面。 大脑疾病和弥合翻译差距的临床。我们的长期目标是开发和使用人类 细胞模型，以阐明相关认知缺陷的分子和细胞机制， NF1表观遗传重编程、干细胞生物学和基因工程领域的最新进展 为我们提供了一个独特的机会来模拟神经发育障碍，如NF 1， 与鼠转基因方法高度互补， contexts.目前研究的目的是利用这些工具来描述 NF 1相关突变引起的神经发育和神经网络活动，并确定 神经纤维蛋白1（NF 1编码蛋白）调节生物学行为的细胞和分子机制 在不同的细胞环境中。根据申请人实验室提供的初步数据，我们 假设NF 1中疾病相关突变影响人的增殖和细胞命运定型 控制神经元输出的神经祖细胞;并通过潜在的 人类特有的机制该假设将使用两种互补的细胞模型进行测试：1）人类 脑类器官将用于研究神经纤维蛋白1在人类神经祖细胞类型中的作用， 特别是在啮齿类动物发育中的皮层中基本上不存在的外部放射状神经胶质细胞。一个多学科 方法将用于表征神经上皮细胞扩增，迁移， 分化以及细胞的有丝分裂特性; 2）诱导神经元（iN）系统，该系统是由 申请人和其他人，将用于剖析不规则神经元网络的细胞机制 在由NF 1突变神经元组成的培养物中观察到活性。目前的研究将是第一个系统的 使用人体模型系统研究神经纤维蛋白1在神经系统中完成所提出的项目功能。这一研究的成功将为神经纤维蛋白1在不同神经系统中的作用提供新的认识。 与NF 1的病理生理学相关的细胞类型。鉴于自闭症在NF 1中的高患病率， 拟议的研究还有可能揭示其背后的关键分子和细胞机制 特发性自闭症