Role of CD44/HA Pathway in Regulation of Neural Stem Cell Fate

描述（由申请人提供）： 胚胎干细胞和体细胞干细胞在理论上对组织再生和人类疾病中器官功能的恢复具有很大的希望。 特别地，人神经干细胞（hNSC）的纯化和表征已经显示出用于神经修复和开发新的基于hNSC的移植策略以治疗神经退行性疾病的潜力。 然而，对局部微环境调节hNSCs命运的机制缺乏了解，反映了我们对基础干细胞生物学知识的差距，仍然是有效治疗的障碍之一。 细胞外基质（ECM）有助于大脑神经微环境的复杂结构。除了提供结构之外，ECM的主要组分透明质酸（HA）通过与由hNSC表达的其细胞表面受体CD 44的相互作用而具有调节功能。 微阵列分析表明，高分子量HA显着改变了24个基因的表达，至少有两个。 MFRP（membrane-type frizzled-related protein）和ICDAP-1 alpha（integrin cytoplasmic domain associated protein-1 alpha）可以决定hNSCs的行为选择。这项K18培训资助申请由伯纳姆研究所干细胞项目主任Evan Snyder博士赞助，旨在解决CD 44/HA通路如何调节hNSCs命运的问题。 基于我们的初步数据，我们假设HA通过与hNSCs上表达的CD 44相互作用并启动随后导致差异基因表达和hNSCs行为重编程的信号转导途径来促进神经源性调控网络。 在具体目标#1中，我们将研究HA对hNSCs中细胞骨架组织和MAPK磷酸化的影响。在具体目标#2中，我们将检查HA对MFRP和ICDAP-1 α表达的影响，以及HA对MFRP和ICDAP-1 α差异表达的影响是否由hNSCs中的CD 44介导。 总的来说，除了提供培训机会外，该提案将使我们能够测试一种新的假设，并为进一步研究CD 44/HA通路在调节hNSCs命运中的作用提供数据。

DESCRIPTION (provided by applicant): Stem cells, both embryonic and somatic, theoretically hold great promise for tissue regeneration and the restoration of organ function in human diseases. In particular, the purification and characterization of human neural stem cells (hNSCs) has shown potential for neural repair and the development of new hNSC-based transplantation strategies for the treatment of aspects of eurodegenerative disorders. However, a lack of understanding of the mechanisms by which the local microenvironment regulates the fate of hNSCs reflects a gap in our knowledge of fundamental stem cell biology and remains one of the obstacles to effective therapies. Extracellular matrix (ECM) contributes to the complex structure of the brain's neurogenic microenvironment. In addition to providing structure, hyaluronic acid (HA), a major component of the ECM, possesses a regulatory function via its interactions with CD44, its cell surface receptor, which is expressed by hNSCs. Micro array analysis suggests that high molecular weight HA significantly changes the expression of 24 genes, at least two. MFRP (membrane-type frizzled-related protein) and ICDAP-1alpha (integrin cytoplasmic domain-associated protein-1 alpha) can determine the behavioral choices of hNSCs. This K18 training grant application, sponsored by Dr. Evan Snyder, director of The Burnham Institute's Stem Cell Program, is designed to address the question of how the CD44/HA pathway regulates the fate of hNSCs. Based on our preliminary data, we hypothesize that HA contributes to the neurogenic regulatory network by interacting with CD44 expressed on hNSCs and initiating signal transduction pathways that subsequently result in differential gene expression and the reprogramming of hNSCs behavior. In Specific Aim #1, we will investigate the effect of HA on cytoskeleton organization and MAPK phosphorylation in hNSCs. In Specific Aim #2, we will examine the effect of HA on the expression of MFRP and ICDAP-1alpha and whether the effect of HA on the differential expression of MFRP and ICDAP-1alpha is mediated by CD44 in hNSCs. Overall, in addition to providing training opportunities, this proposal will allow us to test a novel hypothesis and to generate data for further studies on the role of the CD44/HA pathway in regulation of hNSCs fate.