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和分化为新的神经元、星形胶质细胞和少突胶质细胞。在包括HIV-1相关痴呆（HAD）在内的许多神经退行性疾病中，刺激神经发生对于神经元损伤的恢复是重要的。然而，调控神经发生的机制仍然知之甚少。哺乳动物中枢神经系统（CNS）的主要神经递质谷氨酸在HAD期间在CNS中增加。过量的谷氨酸会引起神经元的兴奋性损伤，但它也可能通过激活α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体（一种嗜离子性谷氨酸受体）来诱导神经发生。我们发现人鼻咽癌表达含有Q/ r -未编辑GluR2亚基的钙渗透性AMPA受体；而NPC分化为神经元和星形胶质细胞表达由Q/ r编辑的GluR2亚基组成的钙不渗透AMPA受体。此外，AMPA受体在鼻咽癌上的激活/增强引导细胞向神经元谱系分化，而不是星形胶质细胞谱系，并增加树突状乔木的发育。在本研究中，我们将探讨AMPA受体介导鼻咽癌分化的机制。我们将开发一个具有诱导表达腺苷脱氨酶（ADAR2）的NPC动物模型，ADAR2是负责GluR2亚基Q/ r编辑的酶，以验证我们的假设，即钙渗透性AMPA受体激活介导NPC向神经元的分化。此外，我们将利用该动物模型来测试使用AMPA受体增强剂作为诱导神经发生手段的可行性。本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。

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).