Regulation of neural stem cells by Lhx2

Lhx2 对神经干细胞的调节

• 批准号: 6895544
• 负责人: LISA A FLANAGAN
• 金额: $ 11.91万
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6895544
• 关键词: Alzheimer' s disease; astrocytes; bromodeoxyuridine; cell differentiation; cell growth regulation; cell proliferation; cerebral cortex; clinical research; developmental genetics; gene expression; genetically modified animals; human tissue; laboratory mouse; nerve stem cell; neurogenesis; neurogenetics; neuroregulation; tissue /cell culture; 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（由申请人提供）：神经干细胞（NSC）为衰老疾病（如阿尔茨海默病）的细胞治疗提供了巨大的希望，因为它们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有助于它们的治疗潜力。由于Lhx2基因敲除小鼠在发育过程中无法形成大脑皮层，因此与这些过程相关的一个分子机制涉及LIM同型结构域转录因子Lhx2的活性。这一发现表明Lhx2是产生皮层分化细胞的NSCs的关键调节因子。在初步数据中，我们发现从Lhx2基因敲除小鼠中分离的NSCs与来自同伴对照的细胞相比增殖不足。Lhx2敲除NSCs的分化表明，与对照小鼠相比，它们产生的神经元更少，神经突（树突和轴突）更短。Lhx2在发育中的灵长类大脑中富含nsc的区域表达，人类Lhx2序列与小鼠99%相同，这表明Lhx2在人类和小鼠中具有相似的功能。本提案的具体目的将验证以下假设：(1)Lhx2调节小鼠NSCs的增殖；(2)Lhx2指导小鼠NSCs的神经元规范和神经突的生长；(3)Lhx2在人类NSCs的增殖和分化中发挥类似的作用。该提案的总体目标是阐明Lhx2在小鼠和人类的NSC增殖、神经元规范和神经突生长中的作用，最终目标是利用这些信息来帮助基于细胞的治疗衰老的神经系统疾病。Lisa Flanagan博士获得了阿尔茨海默病分子机制研究的神经科学博士学位。她随后探索了基础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起来研究NSCs。Flanagan博士的目标是建立一个独立的研究项目来研究NSCs的调控，她将通过与导师、合作者和实验室课程的互动，获得额外的培训，以实现这一目标。她正在加州大学欧文分校进行研究，那里有优秀的资源，可以帮助她实现职业发展和目标。