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: 8634142
• 负责人: David H Gutmann
• 金额: $ 32.26万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634142
• 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）：正常的哺乳动物脑发育涉及祖细胞的调节生长及其分化为专用细胞类型。胚胎发生过程中祖细胞功能异常会导致干细胞群体的不适当扩张和异常的神经胶质成熟，并可能导致许多脑异常，包括儿童脑肿瘤的形成。 1型神经纤维瘤病（NF1）是受影响儿童发生神经胶质细胞肿瘤（光学途径胶质瘤）的最常见遗传条件之一。使用NF1作为模型系统，在体外和体内研究神经茎/祖细胞（NSC）功能，我们已经表明，NF1蛋白（神经纤维蛋白）在胚胎NSC中的丧失会导致（1）增加NSC增殖和自我更新和自我更新，并（2）增加glial linial linial linial liniage膨胀。根据我们的实验观察，我们假设NSC维持和胶质细胞成熟是体内需要神经纤维蛋白。在此提案中，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。该提案的总体目的是利用实验室生成的基因设计的NF1突变小鼠和缺乏NF1的NSC作为可牵引的实验平台来定义在发展中枢神经系统中控制NSC功能的关键控制机制。

项目成果

Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties.

• DOI: 10.1016/j.celrep.2015.02.041
• 发表时间: 2015-03-24
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Chen YH;McGowan LD;Cimino PJ;Dahiya S;Leonard JR;Lee DY;Gutmann DH
• 通讯作者: Gutmann DH

Conditional KIAA1549:BRAF mice reveal brain region- and cell type-specific effects.

• DOI: 10.1002/dvg.22415
• 发表时间: 2013-10
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Kaul, Aparna;Chen, Yi-Hsien;Emnett, Ryan J.;Gianino, Scott M.;Gutmann, David H.
• 通讯作者: Gutmann, David H.

Neurofibromatosis-1 regulation of neural stem cell proliferation and multilineage differentiation operates through distinct RAS effector pathways.

• DOI: 10.1101/gad.261677.115
• 发表时间: 2015-08-15
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Chen YH;Gianino SM;Gutmann DH
• 通讯作者: Gutmann DH

Comparative characterization of the human and mouse third ventricle germinal zones.

• DOI: 10.1097/nen.0b013e31822200aa
• 发表时间: 2011-07
• 期刊: Journal of neuropathology and experimental neurology
• 影响因子: 3.2
• 作者: Dahiya S;Lee DY;Gutmann DH
• 通讯作者: Gutmann DH