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

描述(申请人提供)：正常的哺乳动物大脑发育包括前体细胞的调节生长和分化为特殊的细胞类型。胚胎发育过程中祖细胞功能的异常可能导致干细胞群体的不适当扩张和神经胶质细胞的异常成熟，并可能导致许多脑异常，包括儿童脑瘤的形成。1型神经纤维瘤病(NF1)是儿童发生神经胶质细胞瘤(视路胶质瘤)最常见的遗传性疾病之一。以NF1作为体外和体内研究神经干/祖细胞(NSC)功能的模型系统，我们发现胚胎NSC中NF1蛋白(神经纤维素)功能的丧失导致(1)NSC增殖和自我更新增加，(2)神经胶质系扩张。根据我们的实验观察，我们假设神经纤维蛋白是维持神经干细胞和体内神经胶质细胞成熟所必需的。在这个方案中，我们设计了体外和体内的互补性实验，以确定神经纤维蛋白如何控制神经干细胞的维持和神经胶质细胞的分化。这项建议的总体目标是利用实验室产生的基因工程NF1突变小鼠和NF1缺陷的NSCs作为易于处理的实验平台，以确定在发育中的中枢神经系统中控制NSC功能的关键控制机制。 公共卫生相关性：儿童患脑肿瘤最常见的遗传疾病是1型神经纤维瘤病(NF1)。这项建议使用NF1作为实验模型系统，以了解神经干细胞在与脑瘤形成相关的小鼠正常脑发育中的作用。这些研究可能导致专门针对导致儿童脑瘤的关键生长和命运控制途径的治疗方法的开发。

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. PUBLIC HEALTH RELEVANCE: The most common genetic condition in which children develop brain tumors is neurofibromatosis type 1 (NF1). This proposal employs NF1 as an experimental model system to understand the role of neural stem cells in normal brain development in mice relevant to brain tumor formation. These studies may lead to the development of therapies that specifically target the critical growth and fate control pathways that cause brain tumors in children.