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

描述(申请人提供)：神经前体细胞(NPC)在发育和成年期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相关性痴呆(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具有重要意义。然而，神经发生的调控机制仍然知之甚少。哺乳动物中枢神经系统(CNS)的主要神经递质谷氨酸在HAD时升高。过量的谷氨酸会对神经元造成兴奋性毒性损伤，但它也可能通过激活alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate(AMPA)受体而诱导神经发生。我们发现，人鼻咽癌表达含有Q/R-未编辑的GluR2亚单位的钙通透性AMPA受体，而向神经元分化的鼻咽癌和星形胶质细胞表达由Q/R编辑的GluR2亚基组成的钙不通透性AMPA受体。此外，AMPA受体在鼻咽癌上的激活/增强引导细胞分化为神经元谱系，而不是星形胶质细胞谱系，并促进树突状突起的发育。在本研究中，我们将探讨AMPA受体介导鼻咽癌分化的机制。我们将建立一种可诱导表达腺苷脱氨酶(ADAR2)的鼻咽癌动物模型，腺苷脱氨酶负责GluR2亚单位的Q/R编辑，以验证我们的假设，即钙通透性AMPA受体激活介导了鼻咽癌向神经元的分化。此外，我们将利用这个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。这项研究试图确定谷氨酸诱导神经发生的机制。此外，我们还将研究使用AMPA受体刺激剂作为诱导神经发生的一种手段的可能性。 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，神经再生的诱导对于神经元损伤的恢复至关重要。

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).