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

AMPA 受体与 Q/R-未编辑的 GluR2 在神经发生中的作用

• 批准号: 7496199
• 负责人: Nicholas Paul Whitney
• 金额: $ 3.01万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496199
• 关键词: AIDS Dementia Complex; Affect; Animal Model; Astrocytes; Calcium; Cell Differentiation process; Cell Proliferation; Cells; Chemosensitization; Chronic; Consequences of HIV; Dementia; Development; Enzymes; Glutamate Receptor; Glutamates; HIV Infections; Human; Inflammatory; Knock-in Mouse; Link; Mediating; Modeling; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neurotransmitters; Oligodendroglia; Permeability; Process; Public Health; Receptor Activation; Recovery; Research; Role; Testing; Variant; adenosine deaminase; dsRNA adenosine deaminase; extracellular; nerve stem cell; neurogenesis; receptor; tool

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).

描述（由申请人提供）：神经祖细胞（NPC）能够在发育和成年期间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 相关痴呆 (HAD) 在内的许多神经退行性疾病期间，刺激神经发生对于神经元损伤的恢复非常重要。然而，神经发生的调节机制仍然知之甚少。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 中的谷氨酸含量会增加。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 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。我们发现人类 NPC 表达钙渗透性 AMPA 受体，其中含有 Q/R 未编辑的 GluR2 亚基；而 NPC 分化为神经元和星形胶质细胞，表达由 Q/R 编辑的 GluR2 亚基组成的钙不可渗透的 AMPA 受体。此外，NPC 上 AMPA 受体的激活/增强会引导细胞分化为神经元谱系（而不是星形胶质细胞谱系），并促进树突状乔木的发育。在本研究中，我们将研究 AMPA 受体介导 NPC 分化的机制。我们将开发一种可诱导表达腺苷脱氨酶 (ADAR2)（负责 GluR2 亚基 Q/R 编辑的酶）的 NPC 动物模型，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，我们还将研究使用 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：神经发生的诱导对于许多神经退行性疾病（包括 HIV-1 相关痴呆 (HAD)）期间神经元损伤的恢复非常重要。