Apoptosis and Renewal of Neural Progenitor Cells

描述（由申请人提供）：本申请是我们关于Caspase家族蛋白酶、c-Jun nh2末端激酶（JNK）和磷脂酰丝氨酸受体（PSR）在脑发育和神经系统疾病中神经元凋亡中的作用的研究项目的竞争性更新申请。在本项目中，我们将扩展我们对这些信号通路的研究，并将重点放在神经祖细胞凋亡和更新的机制上。目的1：我们将研究磷脂酰丝氨酸和磷脂酰丝氨酸受体（PS-PSR）识别下游导致神经祖细胞凋亡的机制。我们将在神经祖细胞的外细胞表面表达PS，并研究PS- psr识别后的信号事件。此外，我们将测试胚胎脑中PS-PSR识别的破坏是否会改变神经祖细胞的凋亡。目的2：我们将研究JNK和典型Wnt/ β -连环蛋白信号在神经祖细胞自我更新或细胞周期退出的决定中的相互作用。我们将确定典型的Wnt/ β -catenin通路是否介导自我更新，以及JNK激活是否减弱典型的Wnt/ β -catenin信号传导以促进子细胞的分化。目的3：我们将使用转基因系统来计算小鼠大脑中成年产生的神经元的净增加量。此外，我们将测试EGF和FGF2输注是否可以加速成人神经发生，并将新生神经元吸引到中风损伤的脑区。综上所述，本项目建立在JNK、磷脂基丝氨酸受体（PSR）和典型Wnt/ β -catenin信号的研究基础上，重点研究脑损伤后神经祖细胞数量调节（Aim 1）、神经祖细胞决定细胞周期退出（Aim 2）和神经发生加速（Aim 3）的机制。这些研究将加深我们对脑损伤后神经可塑性和功能恢复的认识。

DESCRIPTION (provided by applicant): This proposal is a competitive renewal application for our research program on the role of the Caspase family of proteases, the c-Jun NH2-terminal kinase (JNK), and the phosphatidylserine receptor (PSR) in neuronal apoptosis in brain development and neurological diseases. In the present project, we will extend our research of these signaling pathways with a new emphasis on the mechanism of apoptosis and renewal of neural progenitor cells. Aim 1: We will investigate the mechanism downstream of phosphatidylserine and phosphatidylserine receptor (PS-PSR) recognition leading to the apoptosis of neural progenitor cells. We will express PS on the outer cell surface of neural progenitor cells and examine the signaling events following PS-PSR recognition. In addition, we will test whether the disruption of PS-PSR recognition in the embryonic brain will alter the apoptosis of neural progenitor cells. Aim 2: We will examine the interaction between the JNK and canonical Wnt/beta-catenin signaling in the decision of self-renewal or cell-cycle exit by neural progenitor cells. We will determine whether the canonical Wnt/beta-catenin pathway mediates self-renewal, and whether JNK activation attenuates the canonical Wnt/ beta-catenin signaling to promote differentiation of the daughter cells. Aim 3: We will use a transgenic system to calculate the net increase of adult-generated neurons in the mouse brain. In addition, we will test whether EGF and FGF2 infusion can accelerate adult neurogenesis and attract newly born neurons into stroke damaged brain areas. In summary, the present project is built on our research of JNK, phosphatidylserine receptor (PSR), and canonical Wnt/beta-catenin signaling with an emphasis on the mechanism governing the adjustment of the number of neural progenitor cells (Aim 1), the decision of cell-cycle exit by neural progenitor cells (Aim 2), and the accelerated neurogenesis after brain injury (Aim 3). These studies will enhance our understanding of neural plasticity and functional recovery after brain injury.