Apoptosis and Renewal of Neural Progenitor Cells

神经祖细胞的凋亡和更新

• 批准号: 7389467
• 负责人: PASKO RAKIC
• 金额: $ 31.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7389467
• 关键词: Address; Adult; Affect; Apoptosis; Apoptotic; Appearance; Area; Attenuated; Book Chapters; Brain; Brain Injuries; Bromodeoxyuridine; Caspase; Cell Cycle; Cell surface; Cells; Chimeric Proteins; Coculture Techniques; Commit; Conflict (Psychology); DNA biosynthesis; DNA chemical synthesis; Development; Disease; Disruption; Embryo; Endopeptidases; Event; FGF2 gene; Family; Fibroblast Growth Factor 2; Fluorescence; Funding; Genetic; Grant; Hematopoietic stem cells; Infusion procedures; JUN gene; Label; Laboratories; Laser Microscopy; Mediating; Methodology; Methods; Microglia; Mitotic; Mus; Neurologic; Neuronal Plasticity; Neurons; Numbers; Paper; Pathway interactions; Peer Review; Peptide Hydrolases; Phagocytosis; Phosphatidylserines; Production; Prosencephalon; Proteins; Publishing; Rate; Recovery of Function; Regulation; Research; Research Personnel; Research Project Grants; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Slice; Standards of Weights and Measures; Stroke; System; Testing; Transgenic Organisms; Work; Xenopus; beta catenin; daughter cell; improved; in vivo; injured; macrophage; migration; multidisciplinary; nerve stem cell; nervous system disorder; neurogenesis; neuron apoptosis; paracrine; phosphatidylserine receptor; postnatal; progenitor; programs; proteoliposomes; receptor; relating to nervous system; self-renewal; stress-activated protein kinase 1; two-photon

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 EOF 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.

该提案是我们关于 Caspase 作用的研究项目的竞争性更新申请 蛋白酶家族、c-Jun NH2 末端激酶 (JNK) 和磷脂酰丝氨酸受体 (PSR) 大脑发育和神经系统疾病中的神经元凋亡。在当前的项目中，我们将扩展 我们对这些信号通路的研究新重点是细胞凋亡和更新机制 神经祖细胞。 目标1：我们将研究磷脂酰丝氨酸和磷脂酰丝氨酸的下游机制 受体（PS-PSR）识别导致神经祖细胞凋亡。我们将在 神经祖细胞的外细胞表面并检查 PS-PSR 识别后的信号事件。 此外，我们将测试胚胎大脑中 PS-PSR 识别的破坏是否会改变 神经祖细胞的凋亡。 目标 2：我们将研究 JNK 与经典 Wnt/β-catenin 信号传导之间的相互作用 神经祖细胞自我更新或细胞周期退出的决定。我们将确定是否规范 Wnt/β-catenin 通路介导自我更新，JNK 激活是否会减弱经典 Wnt/ β-连环蛋白信号传导促进子细胞的分化。 目标 3：我们将使用转基因系统来计算成年神经元的净增加量 老鼠的大脑。此外，我们将测试EOF和FGF2输注是否可以加速成体神经发生 并将新生的神经元吸引到中风受损的大脑区域。 总之，本项目建立在我们对 JNK、磷脂酰丝氨酸受体 (PSR) 和 典型的 Wnt/β-连环蛋白信号传导，重点是控制调节的机制 神经祖细胞的数量（目标 1），神经祖细胞退出细胞周期的决定（目标 2）， 以及脑损伤后加速的神经发生（目标 3）。这些研究将加深我们的理解 脑损伤后神经可塑性和功能恢复的研究。