Integrin/ECM gating of adult neural stem cell activity

描述(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，但它们在神经干细胞生物学中的作用尚不清楚。在这里，我们专注于一种新的整合素-细胞外基质相互作用，它定义了一个允许干细胞自我更新和成年脑内神经发生的环境。神经干细胞在成年哺乳动物的大脑中持续存在，并支持神经元和神经胶质细胞的持续产生。虽然胶质细胞在大脑的所有区域都有产生，但天然的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，例如由损伤，但新神经元的产生和保留是低效的，充其量是流产的。更好地了解当地自然支持干细胞库维持的环境以及干细胞库在神经发生中的有效利用，可能会在神经修复/再生方面取得重大进展。为此，我们已经确定了几种整合素-ECM相互作用，它们选择性地定位于大脑的天然神经源性区域。在体外，我们发现这些相互作用可以控制神经干细胞和前体细胞对有丝分裂原的反应，在这里，我们提出了一些研究，以确定在成人神经源性生态位中使用的特定机制：1)维持和调节干细胞自我更新和干细胞池的大小；2)调节新生成的神经母细胞的瞬时扩增和存活；以及3)调节生理信号，控制海马神经发生对体育锻炼或学习经验的反应。 与公共健康相关：大脑中的神经修复和再生是干细胞研究中最困难但有潜在回报的目标之一。在这一应用中，我们利用大脑中自然产生新神经元的区域来更准确地定义在整个生命中维持干细胞和再生活动的微环境。这种独特的神经源性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和必不可少的。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)评估在新神经元生成背后的现象背后的细胞内信号级联；3)在转基因动物模型中发展和展示这些细胞和分子成分在调节成年神经发生中的作用。我们预计，拟议的研究结果将极大地促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.