Neuroprotective roles for apelin in HIV-associated excitotoxic injury

apelin 在 HIV 相关兴奋性毒性损伤中的神经保护作用

基本信息

批准号：
7924621
负责人：
Denise Rae Cook-Snyder
金额：
$ 4.04万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924621
关键词：
Address Agonist Alzheimer&apos s Disease Antibodies BCL2 gene Binding Biological Assay Blocking Antibodies Brain Brain Hypoxia-Ischemia Calcium Calpain Cell Survival Cells Coupled Coupling D Aspartate Dementia Disease Epilepsy G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Gene Family HIV HIV-1 Hippocampus (Brain)Human Huntington Disease Hypothalamic structure Image Inflammation Inflammatory Injury Insulin-Like Growth Factor I Investigation Ligands Link Mediating Mitogen-Activated Protein Kinase 3 N-Methyl-D-Aspartate Receptors Neuraxis Neurocognitive Neurodegenerative Disorders Neuronal Injury Neurons Neuropeptides Parkinson Disease Pathway interactions Peptide Hydrolases Peripheral Phosphorylation Phosphotransferases Play Predisposition Proteins RNA Receptor Activation Receptor Protein-Tyrosine Kinases Rodent Role Signal Pathway Signal Transduction Signal Transduction Pathway Therapeutic Tissues Toxic effect Transactivation Virus Diseases Western Blotting aspartate receptor base chemokine receptor improved in vitro Model neuronal survival neuroprotection neurotoxicity novel public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): Excitotoxic neuronal injury via activation of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in a variety of neurodegenerative disorders, including human immunodeficiency virus (HIV)-associated neurocognitive disorders (IHAND). The broad objective of this proposal is to improve our understanding of signaling pathways that promote neuronal survival against HIV-induced neurotoxicity, thereby enhancing our ability to develop therapeutics for HAND and related neurodegenerative disorders. In vitro modeling of HIV-induced neurotoxicity demonstrates that activation of certain neuronal G-protein coupled receptors (GPCRs), such as chemokine receptors, can counteract excitotoxic neuronal injury through modulation of cell survival signaling pathways. The APJ receptor is a recently described GPCR that, like chemokine receptors, can serve as a co-receptor for HIV entry in certain cells. Furthermore, APJ and its ligand apelin are highly expressed in the central nervous system (CNS), suggesting that apelin/APJ signaling could play a central role in modulating CNS responses to HIV-induced neurotoxicity. Our preliminary investigations suggest that apelin release following inflammatory- and/or NMDAR-mediated neuronal activation counteracts HIV-induced neurotoxicity via activation of cell survival kinases. Based on these findings, we hypothesize that apelin, acting as a soluble neuropeptide through APJ, activates a novel, endogenous neuronal survival response that integrates several cell survival signaling pathways following inflammatory- and/or NMDAR-mediated neuronal activation during HIV infection. Therefore, in this proposal, we will determine the mechanism(s) of apelin-mediated neuroprotection. Specific Aim 1 will use ELISAs and an antibody-based microarray to define the cell survival signaling pathways modulated by apelin/APJ interactions. Specific Aim 2 will identify an apelin function blocking antibody and use ELISAs, PCR, and an immunofluorescent neurotoxicity assay to identify functional changes in apelin expression and release during HIV-induced neurotoxicity. Specific Aim 3 will use calcium imaging and Western blotting to identify potential roles for apelin in modulating NMDAR-mediated excitotoxic cell signaling. PUBLIC HEALTH RELEVANCE: Excitotoxic neuronal injury has been implicated in a variety of neurodegenerative disorders, including hypoxia/ischemia, epilepsy, Huntington's Disease, Parkinson's Disease, Alzheimer's Disease, and HIV-associated neurocognitive disorders (HAND). By improving our understanding of signal transduction pathways that promote neuronal survival against HIV-induced toxicity, we hope to enhance our ability to develop therapeutics for HAND and related neurodegenerative disorders.

描述（由申请人提供）：通过激活N-甲基-D-天冬氨酸受体（NMDAR）激活兴奋性神经元损伤已与多种神经退行性疾病有关，包括人类免疫缺陷病毒（HIV）相关的神经认知疾病（IHIV）。该提案的广泛目标是提高我们对促进艾滋病毒诱导神经毒性的神经元存活的信号通路的理解，从而增强我们开发用于手和相关神经退行性疾病的治疗疗法的能力。 HIV诱导的神经毒性的体外模型表明，某些神经元G蛋白偶联受体（GPCR）的激活（例如趋化因子受体）可以通过调节细胞存活信号通路来抵消兴奋性神经元损伤。 APJ受体是最近描述的GPCR，它像趋化因子受体一样可以作为某些细胞中HIV进入的共受体。此外，APJ及其配体APELIN在中枢神经系统（CNS）中高度表达，这表明APELIN/APJ信号传导在调节CNS对HIV诱导的神经毒性的反应中可能起核心作用。我们的初步研究表明，炎症性和/或NMDAR介导的神经元激活后，Apelin释放，通过激活细胞存活激酶来抵消HIV诱导的神经毒性。基于这些发现，我们假设Apelin通过APJ充当可溶性神经肽，激活了一种新型的内源性神经元存活反应，该反应在HIV感染过程中整合了炎症性和/或NMDAR介导的神经元激活后的几个细胞存活信号通路。因此，在此提案中，我们将确定Apelin介导的神经保护的机制。特定的目标1将使用ELISA和基于抗体的微阵列来定义由Apelin/apj相互作用调节的细胞存活信号通路。特定的目标2将识别丙链蛋白函数阻断抗体并使用ELISA，PCR和免疫荧光神经毒性测定法，以鉴定HIV诱导的神经毒性期间Apelin表达和释放的功能变化。特定的目标3将使用钙成像和蛋白质印迹来鉴定阿位蛋白在调节NMDAR介导的兴奋性细胞信号传导中的潜在作用。公共卫生相关性：兴奋性神经元损伤与多种神经退行性疾病有关，包括低氧/缺血，癫痫，亨廷顿氏病，帕金森氏病，阿尔茨海默氏病以及与HIV相关的神经认知疾病（手）。通过提高我们对促进艾滋病毒诱导毒性神经元存活的信号转导途径的理解，我们希望增强我们为手和相关神经退行性疾病开发治疗疗法的能力。