Integrin/ECM gating of adult neural stem cell activity

描述（由申请人提供）：整合素及其与细胞外基质蛋白（ECM）的相互作用调节许多细胞过程，但其在神经干细胞生物学中的作用尚不清楚。在这里，我们专注于一个新的整合素ECM的相互作用，定义了一个允许的环境干细胞自我更新和神经发生在成年人的大脑。神经干细胞存在于成年哺乳动物的大脑中，并支持神经元和神经胶质的持续产生。虽然胶质细胞在大脑的所有区域都有产生，但天然神经发生仅限于脑室下区（SVZ）和海马颗粒下区（SGZ）。神经发生可以在大脑的其他区域被触发，例如通过损伤，但是新神经元的产生和保留是低效的，充其量是流产。更好地了解自然支持维持干细胞库的局部环境以及它们在神经发生中的有效利用可能会导致神经修复/再生的重大进展。为此，我们已经确定了几个整合素-ECM的相互作用，选择性地定位于大脑的天然神经原性区域。在体外，我们发现这些相互作用门神经干细胞和祖细胞对有丝分裂原的反应，在这里，我们提出研究，以确定在成人神经原性生态位内使用的具体机制：1）维持和调节干细胞自我更新和干细胞池的大小; 2）调节新产生的神经母细胞的瞬时扩增和存活;和3）介导生理信号传导，其响应于体育锻炼或学习经历而控制海马神经发生。 公共卫生相关性：大脑中的神经修复和再生是干细胞研究中最困难但最有潜力的目标之一。在这个应用中，我们利用大脑中自然产生新神经元的区域，更精确地定义了维持干细胞和再生活性的微环境。这种独特的神经生态位利用细胞和信号的复杂相互作用来维持和调节神经发生，我们最近发现细胞外基质蛋白在这种细胞和生化环境中是不可或缺的。在这里，我们建议1）进一步完善我们对促进或抑制干细胞在新神经元的产生，存活和整合中的分子相互作用的理解; 2）评估新神经元产生背后现象的细胞内信号级联; 3）开发和证明这些细胞和分子组分在转基因动物模型中调节成体神经发生中的作用。我们预计，拟议研究的结果将大大推进我们对自然再生过程的理解，并为提高未来干细胞疗法对各种神经损伤和疾病的疗效提供见解。

DESCRIPTION (provided by applicant): Integrins and their interactions with extracellular matrix proteins (ECM) regulate many cellular processes but their role in neural stem cell biology is poorly defined. Here we focus on a novel integrin-ECM interaction that defines a permissive environment for stem cell self-renewal and neurogenesis in the adult brain. Neural stem cells persist in the adult mammalian brain and support the continuing production of neurons and glia. Although glia are produced in all areas of the brain, native neurogenesis is restricted to the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Neurogenesis can be triggered in other areas of the brain, for example by injury, but the production and retention of new neurons is inefficient and abortive at best. A better understanding of local environments that naturally support the maintenance of a stem cell pool as well as their efficient use in neurogenesis could lead to significant advances in neural repair/regeneration. Toward this end, we have identified several integrin-ECM interactions that are selectively localized to the native neurogenic areas of the brain. In vitro, we show that these interactions gate neural stem and progenitor cell response to mitogens and here we propose studies to define the specific mechanisms used within the adult neurogenic niche to: 1) maintain and regulate stem cell self-renewal and stem cell pool size; 2) regulate the transient amplification and survival of newly generated neuroblasts; and 3), mediate physiological signaling that controls hippocampal neurogenesis in response to physical exercise or learning experiences. PUBLIC HEALTH RELEVANCE: Neural repair and regeneration in the brain is one of the most difficult yet potentially rewarding goals in stem cell research. In this application we take advantage of an area of the brain that naturally produces new neurons to more precisely define the microenvironment that maintains stem cells and regenerative activity throughout life. This unique neurogenic niche utilizes a complex interaction of cells and signals to maintain and regulate neurogenesis and we have recently found that extracellular matrix proteins are integral and essential in this cellular and biochemical environment. Here we propose to 1) further refine our understanding of the molecular interactions that promote or inhibit the stem cells in the generation, survival and integration of new neurons; 2) evaluate the intracellular signaling cascades that underlie the phenomenon behind the generation of new neurons; 3) develop and demonstrate the role of these cellular and molecular components in regulating adult neurogenesis in transgenic animal models. We anticipate that the outcome of the proposed studies will significantly advance our understanding of natural regenerative processes and provide insights into improving the efficacy of future stem cell therapies for a variety of neurological injuries and diseases.