The Role of AMPA Receptors with Q/R-Unedited GluR2 in Neurogenesis

描述（由申请人提供）：神经祖细胞（NPC）在发育和成年期间能够自我更新并分化为新的神经元、星形胶质细胞和少突胶质细胞。在包括HIV-1相关性痴呆（HAD）在内的许多神经退行性疾病中，神经发生的刺激对于神经元损伤的恢复将是重要的。然而，神经发生的调控机制仍然知之甚少。谷氨酸是哺乳动物中枢神经系统（CNS）中的主要神经递质，在HAD期间CNS中增加。过量的谷氨酸会引起神经元的兴奋性毒性损伤，但它也可能通过激活α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）受体（一种离子型谷氨酸受体）诱导神经发生。我们已经发现，人NPC表达含有Q/R-未编辑的GluR 2亚基的钙渗透性AMPA受体;而分化为神经元和星形胶质细胞的NPC表达由Q/R-编辑的GluR 2亚基组成的钙渗透性AMPA受体。此外，NPC上AMPA受体的激活/增强指导细胞分化为神经元谱系而不是星形胶质细胞谱系，并增加树突状细胞的发育。在本研究中，我们将探讨AMPA受体介导NPC分化的机制。我们将开发具有腺苷脱氨酶（ADAR 2）（负责GluR 2亚基的Q/R编辑的酶）的诱导表达的NPC动物模型，以验证我们的假设，即钙渗透性AMPA受体活化介导NPC向神经元的分化。此外，我们将利用这种动物模型来测试使用AMPA受体增强剂作为诱导神经发生的手段的可行性。这项研究旨在确定谷氨酸诱导神经发生的机制。此外，我们将研究使用AMPA受体刺激剂作为诱导神经发生的手段的可能性。 公共卫生相关性：在包括HIV-1相关性痴呆（HAD）在内的许多神经退行性疾病中，神经发生的诱导对于神经元损伤的恢复将是重要的。

DESCRIPTION (provided by applicant): Neural progenitor cells (NPC) are capable of self-renewing and differentiating into new neurons, astrocytes, and oligodendrocytes during development and adulthood. Stimulation of neurogenesis would be important to the recovery from neuronal injury during many neurodegenerative disorders including HIV-1 Associated Dementia (HAD). However, the mechanisms by which neurogenesis is regulated remain poorly understood. Glutamate, the primary neurotransmitter in the mammalian central nervous system (CNS) is increased in the CNS during HAD. Excess glutamate causes excitotoxic damage to neurons, however it may also induce neurogenesis through the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, an ionotropic glutamate receptor. We have found that human NPC express calcium-permeable AMPA receptors containing Q/R-unedited GluR2 subunits; whereas, NPC differentiated to neurons and astrocytes express calcium-impermeable AMPA receptors comprised of Q/R-edited GluR2 subunits. In addition, the activation/potentiation of AMPA receptors on NPC directs the cells to differentiate to the neuronal lineage as opposed to the astrocyte lineage and increases the development of dendritic arbors. In this study we will investigate the mechanisms through which AMPA receptors mediate differentiation of NPC. We will develop an animal model with NPC with inducible expression of adenosine deaminase (ADAR2), the enzyme responsible for Q/R-editing of GluR2 subunits, to verify our hypothesis that calcium- permeable AMPA receptor activation mediates the differentiation of NPC to neurons. Furthermore, we will utilize this animal model to test the feasibility of using AMPA receptor potentiators as a means to induce neurogenesis. This research seeks to identify a mechanism through which glutamate induces neurogenesis. Also, we will examine the possibility of using AMPA receptor stimulators as a means to induce neurogenesis. PUBLIC HEALTH RELEVANCE: The induction of neurogenesis would be important to the recovery from neuronal injury during many neurodegenerative disorders including HIV-1 Associated Dementia (HAD).