The Role of Neural Stem Cells in Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是儿童和成人中最常见的后天性脑损伤类型。迄今为止，我们对TBI的病理学和治疗的大部分见解都集中在创伤后发生的区域生理学上。然而，我们对这种损伤后在细胞和分子水平上发生的事情的了解是有限的。最近，内源性神经干细胞已被牵连在各种类型的脑损伤后发生的细胞重塑。我们最近使用TBI小鼠模型证明，神经干细胞增殖，迁移到并帮助重塑大脑的受损区域。然而，目前还不清楚神经干细胞在多大程度上促成了这种重塑，以及这种贡献是否以功能上有用的方式发生。这项建议将集中在小鼠海马TBI的分子建模，以确定内源性神经干细胞对海马损伤后恢复的作用。在具体目标1中，我们将量化TBI后海马中干细胞增殖的幅度和时间过程。我们将使用一种转基因动物来做这件事，我们已经开发并鉴定了这种转基因动物只在成年神经祖细胞中表达GFP。在具体目标2中，我们将确定TBI后的功能恢复是否依赖于海马干细胞增殖。我们将使用我们最近开发的小鼠遗传模型进行功能获得和丧失研究。这些包括上文提及的nestin-rtTA-GFP小鼠以及在损伤后受到神经保护并且具有丰富的神经干细胞的Bax缺陷小鼠。最后，在具体目标3中，我们将确定细胞内钙如何影响海马神经干细胞的存活。我们将使用器官型海马培养物并通过测量单个神经干细胞中钙流量如何受细胞调节因子（如IP 3受体）影响来进行离体研究。 后天性脑损伤，如创伤造成的脑损伤，是所有年龄组死亡和长期残疾的最常见原因之一。目前还不清楚神经干细胞是否是造成这种损伤后自发发生的一些有限恢复的原因。在这项提案中，我们不仅将定义干细胞在创伤性脑损伤后恢复中的作用，还将确定如何操纵这些细胞以改善损伤后的恢复。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the most common type of acquired brain injury in both children and adults. To date, most of our insight into the pathology and treatment of TBI has focused on the regional physiology that occurs following trauma. Our knowledge about what happens at the cellular and molecular level following such injuries, however, is limited. Recently, endogenous neural stem cells have been implicated in the cellular remodeling that occurs following various types of brain injury. We recently demonstrated, using a mouse model of TBI, that neural stem cells proliferate, migrate to, and help remodel injured areas of the brain. It is still unclear, however, how much neural stem cells contribute to this remodeling and whether this contribution occurs in a functionally useful way. This proposal will focus on molecularly modeling TBI in the mouse hippocampus in order to determine the role of endogenous neural stem cells on hippocampal recovery after injury. In Specific Aim 1, we will quantify the magnitude and time course of stem cell proliferation in the hippocampus following TBI. We will do this using a transgenic animal that we have developed and characterized that expresses GFP exclusively in adult neural progenitor cells. In Specific Aim 2, we will determine whether functional recovery following TBI depends on hippocampal stem cell proliferation. We will do this using gain- and loss-of-function studies with mouse genetic models that we have recently developed. These include the nestin-rtTA-GFP mouse referenced above as well a Bax- deficient mouse that is neuroprotected following injury and has an abundance of neural stem cells. Finally, in Specific Aim 3, we will determine how intracellular calcium affects the survival of hippocampal neural stem cells. We will do this ex-vivo using organotypic hippocampal cultures and by measuring in individual neural stem cells how calcium flux is affected by cellular regulators such as the IP3 receptor. Acquired brain injuries, such as those resulting from trauma, are among the most common causes death and long-term disability in all age groups. It is unclear whether neural stem cells are responsible for some of the limited recovery that spontaneously occurs following such injuries. In this proposal, we will not only define the role that stem cells play in recovery following traumatic brain injury, but also identify how these cells might be manipulated to improve recovery after injury.