Regulation of neural stem cells by Lhx2

Lhx2 对神经干细胞的调节

• 批准号: 7447371
• 负责人: LISA A FLANAGAN
• 金额: $ 12.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7447371
• 关键词: Aging; Alzheimer' s Disease; Amino Acid Sequence; Area; Astrocytes; Award; Axon; Brain; Cell Differentiation process; Cell Proliferation; Cell Therapy; Cells; Cellular biology; Cerebral cortex; Cytoskeleton; Data; Defect; Dendrites; Development; Disease; Doctor of Philosophy; Generations; Goals; Human; In Vitro; Knock-out; Knockout Mice; Laboratories; Mentors; Molecular; Mus; Neuraxis; Neurites; Neuronal Differentiation; Neurons; Neurosciences; Oligodendroglia; Pathway interactions; Pattern; Peptide Sequence Determination; Phenotype; Play; Primates; Process; Production; Proliferating; Regulation; Replacement Therapy; Research; Resources; Role; Specific qualifier value; Staging; Stem Cell Development; Testing; Therapeutic; Training; Work; base; career; cell cortex; cell type; daughter cell; gain of function; homeodomain; in vivo; interest; nerve stem cell; nervous system disorder; neurogenesis; programs; research study; transcription factor

DESCRIPTION (provided by applicant): Neural stem cells (NSC's) provide great promise for cell-based therapies for diseases of aging, such as Alzheimer's disease, because they self-renew and form the three main cell types of the central nervous system: neurons, astrocytes, and oligodendrocytes. A basic understanding of the molecular mechanisms that control the proliferation and differentiation of these cells will greatly aid their therapeutic potential. One molecular mechanism implicated in these processes involves the activity of the LIM homeodomain transcription factor Lhx2, since Lhx2 knockout mice are unable to form a cerebral cortex during development. This finding suggests that Lhx2 is a critical regulator of the NSCs that generate the differentiated cells of the cortex. In preliminary data we show that NSCs isolated from Lhx2 knockout mice are deficient in proliferation compared to cells from littermate controls. Differentiation of Lhx2 knockout NSCs reveals that they produce fewer neurons with shorter neurites (dendrites and axons) than cells from control mice. Lhx2 is expressed in NSC-rich regions of the developing primate brain and the human Lhx2 sequence is 99% identical to the mouse, suggesting that Lhx2 performs similar functions in humans and mice. The specific aims of this proposal will test the following hypotheses: (1) Lhx2 regulates proliferation of mouse NSCs, (2) Lhx2 directs neuronal specification and neurite outgrowth of mouse NSCs, and (3) Lhx2 plays similar roles in the proliferation and differentiation of human NSCs. The overall goal of this proposal is to clarify the role of Lhx2 in NSC proliferation, neuronal specification, and neurite outgrowth in mice and humans with the eventual goal of using this information to aid cell-based therapeutics for neurological diseases of aging. Dr. Lisa Flanagan, Ph.D., earned her doctoral degree in neuroscience studying molecular mechanisms of Alzheimer's disease. She subsequently explored basic cell biology and the cytoskeleton and is now combining these areas of expertise in the study of NSCs. Dr. Flanagan's goal is to establish an independent research program to investigate the regulation of NSCs, and she will receive additional training through this award toward this goal by her interaction with mentors, collaborators, and laboratory coursework. She is pursuing her research at UC Irvine, which has outstanding resources that will aid her in her career development and goals.

描述(申请人提供)：神经干细胞(NSC)为老年性疾病(如阿尔茨海默病)的基于细胞的治疗提供了巨大的希望，因为它们可以自我更新并形成中枢神经系统的三种主要细胞类型：神经元、星形胶质细胞和少突胶质细胞。对控制这些细胞增殖和分化的分子机制的基本了解将极大地帮助它们的治疗潜力。这些过程中涉及的一个分子机制涉及LIM同源结构域转录因子LHX2的活性，因为LHX2基因敲除的小鼠在发育过程中无法形成大脑皮层。这一发现表明，LHX2是神经干细胞的关键调节因子，神经干细胞产生皮质分化的细胞。在初步数据中，我们发现，从LHX2基因敲除小鼠分离的神经干细胞与产仔对照的细胞相比，在增殖方面存在缺陷。对LHX2基因敲除的神经干细胞的分化显示，它们产生的神经元比对照组小鼠的细胞产生的神经元更少，突起(树突和轴突)更短。LHX2在发育中的灵长类动物大脑中富含神经干细胞的区域表达，人类的LHX2序列与小鼠的序列有99%的同源性，这表明LHX2在人类和小鼠中具有类似的功能。该方案的具体目的将检验以下假设：(1)LHX2调节小鼠NSCs的增殖；(2)LHX2指导小鼠NSCs的神经元分化和突起生长；(3)LHX2在人NSCs的增殖和分化中发挥类似的作用。这项提案的总体目标是阐明LHX2在小鼠和人类神经干细胞增殖、神经元规范和轴突生长中的作用，最终目标是利用这些信息帮助基于细胞的治疗衰老的神经疾病。丽莎·弗拉纳根博士获得了神经科学博士学位，研究阿尔茨海默病的分子机制。她随后探索了基本的细胞生物学和细胞骨架，现在正在将这些领域的专业知识结合到神经干细胞的研究中。弗拉纳根博士的目标是建立一个独立的研究计划来调查神经干细胞的监管，她将通过这个奖项接受额外的培训，通过她与导师、合作者和实验室课程的互动来实现这一目标。她正在加州大学欧文分校从事研究，该校拥有丰富的资源，将帮助她实现职业发展和目标。

项目成果

Advancing practical usage of microtechnology: a study of the functional consequences of dielectrophoresis on neural stem cells.

• DOI: 10.1039/c2ib20171b
• 发表时间: 2012-10
• 期刊: Integrative biology : quantitative biosciences from nano to macro
• 作者: Lu J;Barrios CA;Dickson AR;Nourse JL;Lee AP;Flanagan LA
• 通讯作者: Flanagan LA

Salmon fibrin treatment of spinal cord injury promotes functional recovery and density of serotonergic innervation.

• DOI: 10.1016/j.expneurol.2012.02.016
• 发表时间: 2012-05
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Sharp, Kelli G.;Dickson, Amanda R.;Marchenko, Steve A.;Yee, Kelly M.;Emery, Pauline N.;Laidmae, Ivo;Uibo, Raivo;Sawyer, Evelyn S.;Steward, Oswald;Flanagan, Lisa A.
• 通讯作者: Flanagan, Lisa A.