NEUROFIBROMIN REGULATION OF NEURAL STEM CELL FUNCTION IN VITRO AND IN VIVO

神经纤维蛋白对体外和体内神经干细胞功能的调节

• 批准号: 8424310
• 负责人: David H Gutmann
• 金额: $ 31.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-04 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424310
• 关键词: Affect; Astrocytes; Biological Models; Brain; Brain Diseases; Brain Neoplasms; Brain Stem; Brain region; Cell Differentiation process; Cell Maintenance; Cell Maturation; Cell Proliferation; Cell physiology; Child; Critical Pathways; Development; Embryo; Embryonic Development; Exhibits; Experimental Models; Genetic Engineering; Genetically Engineered Mouse; Glial Differentiation; Glioma; Goals; Growth; Hereditary Disease; In Vitro; Individual; Laboratories; Lead; Location; MAP Kinase Gene; MEK inhibition; MEKs; Mediating; Mouse Strains; Mus; Mutant Strains Mice; NF1 gene; Neocortex; Neuraxis; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Neuroglia; Optic Nerve; Optics; Pathway interactions; Protein Isoforms; Proteins; Ras/Raf; Regulation; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stem cells; Testing; base; cell type; design; gliogenesis; human NCOR1 protein; human TSC1 protein; in vivo; mTOR protein; nerve stem cell; neuroregulation; progenitor; public health relevance; relating to nervous system; research study; self-renewal; stem; stem cell population; therapy development; transcription factor

DESCRIPTION (provided by applicant): Normal mammalian brain development involves the regulated growth of progenitor cells and their differentiation into specialized cell types. Abnormalities in progenitor cell function during embryogenesis can lead to inappropriate expansion of stem cell populations and abnormal glial maturation, and potentially result in a number of brain abnormalities, including the formation of brain tumors in children. Neurofibromatosis type 1 (NF1) is one of the most common genetic conditions in which affected children develop glial cell tumors (optic pathway gliomas). Using NF1 as a model system to study neural stem/progenitor cell (NSC) function in vitro and in vivo, we have shown that loss of Nf1 protein (neurofibromin) function in embryonic NSCs results in (1) increased NSC proliferation and self-renewal and (2) increased glial lineage expansion. Based on our experimental observations, we hypothesize that neurofibromin is required for NSC maintenance and glial cell maturation in vivo. In this proposal, we have designed complementary in vitro and in vivo experiments to determine how neurofibromin controls NSC maintenance and glial cell differentiation. The overall objective of this proposal is to employ laboratory-generated genetically-engineered Nf1 mutant mice and Nf1-deficient NSCs as tractable experimental platforms to define the critical control mechanisms that govern NSC function in the developing central nervous system.

描述（由申请人提供）：正常哺乳动物大脑发育涉及祖细胞的调节生长及其分化为特殊细胞类型。胚胎发生过程中祖细胞功能的异常可能导致干细胞群体的不当扩张和神经胶质成熟的异常，并可能导致许多大脑异常，包括儿童脑肿瘤的形成。 1 型神经纤维瘤病 (NF1) 是最常见的遗传性疾病之一，受影响的儿童会患上神经胶质细胞瘤（视神经胶质瘤）。使用 NF1 作为模型系统在体外和体内研究神经干/祖细胞 (NSC) 功能，我们发现胚胎 NSC 中 Nf1 蛋白（神经纤维蛋白）功能的丧失会导致 (1) NSC 增殖和自我更新增加(2) 神经胶质谱系扩张增加。根据我们的实验观察，我们假设神经纤维蛋白是 NSC 维持和体内神经胶质细胞成熟所必需的。在本提案中，我们设计了互补的体外和体内实验，以确定神经纤维蛋白如何控制 NSC 维持和神经胶质细胞分化。该提案的总体目标是利用实验室生成的基因工程 Nf1 突变小鼠和 Nf1 缺陷型 NSC 作为易于处理的实验平台，以定义控制发育中的中枢神经系统中 NSC 功能的关键控制机制。