Stem Cells And Neurogenesis

干细胞和神经发生

• 批准号: 7591990
• 负责人: Mark Mattson
• 金额: $ 78.17万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7591990
• 关键词: Adult; Applied Research; Astrocytes; Behavior; Bone Morphogenetic Proteins; Brain-Derived Neurotrophic Factor; CXCR4 gene; Cell Aging; Cell Differentiation process; Cells; Clinical; Condition; Databases; Development; Developmental Process; Differentiation Antigens; Disease; ES Cell Line; Embryo; Enhancers; Feedback; Future; Genes; Glial Differentiation; Homeodomain Proteins; Homologous Gene; Human; Injury; Knowledge; Laboratories; Lead; Modeling; Molecular; Multiple Sclerosis; Multiple Trauma; Multipotent Stem Cells; Mus; Nervous system structure; Neuraxis; Neurons; Nitric Oxide; Oligodendroglia; Production; Property; Rattus; Role; Signal Transduction Pathway; Source; Stem Cell Factor; Stem cells; Transgenic Model; Transgenic Organisms; Translating; Transplantation; Traumatic Brain Injury; Work; adult stem cell; base; cell age; cell population study; dopaminergic differentiation; embryonic stem cell; human embryonic stem cell; human embryonic stem cell line; in utero; in vitro Assay; in vivo; migration; mouse Neurog3 protein; nerve stem cell; neurogenesis; novel; novel strategies; precursor cell; protocol development; relating to nervous system; response; stem; tool

Multipotent stem cells and more developmentally restricted precursors have previously been isolated from the developing nervous system, and their properties analyzed by culture assays in vitro and by transplantation in vivo. My laboratory has continued its analysis of embryonic stem cells and the factors regulating their differentiation into neurons, astrocytes and oligodendrocytes. Our current work is split between studying neural stem and progenitor cells, growing and characterizing human and mouse ES cells and developing new tools to study these cell populations. Our focus on ES cells is based on the realization that translating our findings to the clinical arena will require developing a reliable and reproducible source of cells. Our work on neural stem and progenitor cells is focused on identifying novel genes or novel roles of known genes, that may regulate the developmental process and extending the analysis of the behavior of stem cells in adult models of injury and disease. A long-term plan is to develop rat transgenic models, rat ES cell lines, and in-utero transplant paradigms. Recent results include a) Demonstrating neural differentiation of human ES (embryonic stem) cells b) Demonstrating a role for Nkx2.2 (Homeodomain protein) and ngn-3 (neurogenin-3) in regulating oligodendrocye differentiation c) Showing that Hes-1 (enhancer of split homologue), Hes-5 and BMP?s (Bone morphogenetic protein) regulate astrocyte differentiation from glial progenitor cells d) Identifying markers for neural stem cells e) Developing a stem cell microarray f) Generating a transgenic rat . Our more recent focus on human ES cells has lead to the development of feeder free culture conditions for ES cells, the establishment fo a database of ES and EB specific markers and the development of protocols for dopaminergic differentiation of cells. Together these results provide a strong basis for understanding how stem and precursor cell differentiation is regulated. Our model of differentiation suggests a sequential acquisition of differentiation markers. Our future work will focus on extending these observations and understanding how stem cells age. We have also made considerable progress towards understanding the cellular and molecular mechanisms that regulate the prolliferation, differentiation and survival of neural progenitor cells in the developing and adult central nervous system. We have found that nitric oxide and BDNF function in a positive feedback loop to promote neurogenesis. In other studies we found that SDFalpha, activates CXCR4 in glial progenitor cells resulting in increased migration and differentation of those cells. We have also investigated the roles of glial progenitor cells in the response of the nervous system to injury in models of traumatic brain injury and multiple sclerosis.

多能干细胞和更多发育受限的前体细胞以前已从发育中的神经系统中分离出来，并通过体外培养试验和体内移植分析了它们的特性。我的实验室继续分析胚胎干细胞和调节它们分化成神经元、星形胶质细胞和少突胶质细胞的因子。我们目前的工作分为研究神经干细胞和祖细胞，培养和表征人类和小鼠ES细胞以及开发研究这些细胞群的新工具。我们对ES细胞的关注是基于这样一种认识，即将我们的发现转化为临床竞技场将需要开发一种可靠且可重复的细胞来源。我们在神经干细胞和祖细胞方面的工作重点是识别新基因或已知基因的新作用，这些基因可能调节发育过程，并扩展对成人损伤和疾病模型中干细胞行为的分析。长期计划是开发大鼠转基因模型、大鼠ES细胞系和子宫内移植范例。最近的结果包括：a）证明人ES（胚胎干）细胞的神经分化B）证明Nkx 2.2（同源结构域蛋白）和ngn-3（神经原蛋白-3）在调节少突胶质细胞分化中的作用c）表明Hes-1（分裂同源物增强子）、Hes-5和BMP？s（骨形态发生蛋白）调节胶质祖细胞向星形胶质细胞分化d）鉴定神经干细胞的标记e）开发干细胞微阵列f）产生转基因大鼠。 我们最近对人ES细胞的关注导致了ES细胞的无饲养层培养条件的发展，ES和EB特异性标志物数据库的建立以及细胞多巴胺能分化方案的发展。 这些结果为理解干细胞和前体细胞分化是如何被调节的提供了强有力的基础。我们的分化模型表明，分化标记物的顺序收购。我们未来的工作将集中在扩展这些观察和理解干细胞如何老化。 我们也取得了相当大的进展，了解细胞和分子机制，调节神经祖细胞的增殖，分化和生存的发展和成人中枢神经系统。 我们已经发现，一氧化氮和BDNF的功能，在一个积极的反馈回路，以促进神经发生。 在其他研究中，我们发现SDF α激活神经胶质祖细胞中的CXCR 4，导致这些细胞的迁移和分化增加。 我们还研究了神经胶质祖细胞在创伤性脑损伤和多发性硬化模型中神经系统对损伤的反应中的作用。

项目成果

Isolation of stem and precursor cells from fetal tissue.

从胎儿组织中分离干细胞和前体细胞。

• DOI: 10.1385/1-59259-186-8:029
• 发表时间: 2002
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Wu,YuanY;Mujtaba,Tahmina;Rao,MahendraS
• 通讯作者: Rao,MahendraS

Isolation of lineage-restricted neural precursors from cultured ES cells.

从培养的 ES 细胞中分离谱系限制的神经前体细胞。

• DOI: 10.1385/1-59259-241-4:189
• 发表时间: 2002
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Mujtaba,T;Rao,MS
• 通讯作者: Rao,MS

Monitoring early differentiation events in human embryonic stem cells by massively parallel signature sequencing and expressed sequence tag scan.

• DOI: 10.1089/scd.2004.13.694
• 发表时间: 2004-12
• 期刊: Stem cells and development
• 影响因子: 4
• 作者: T. Miura;Yongquan Luo;I. Khrebtukova;R. Brandenberger;Daixing Zhou;R. Thies;T. Vasicek;Holly Y. Young;J. Lebkowski;M. Carpenter;M. Rao

Stem and precursor cells in the nervous system.

• DOI: 10.1089/089771504323004566
• 发表时间: 2004-07
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: M. Rao

Transcriptome coexpression map of human embryonic stem cells.

• DOI: 10.1186/1471-2164-7-103
• 发表时间: 2006-05-02
• 期刊: BMC GENOMICS
• 影响因子: 4.4
• 作者: Li, Huai;Liu, Ying;Shin, Soojung;Sun, Yu;Loring, Jeanne F;Mattson, Mark P;Rao, Mahendra S;Zhan, Ming
• 通讯作者: Zhan, Ming