Elucidating the role of Ephrin-b1 in Interferon Beta (IFN-beta) mediated neuroprotection in HIV associated neurocognitive disorder (HAND)

阐明 Ephrin-b1 在干扰素 Beta (IFN-beta) 介导的 HIV 相关神经认知障碍 (HAND) 神经保护中的作用

• 批准号: 10548011
• 负责人: Jeffrey Koury
• 金额: $ 3.9万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548011
• 关键词: Ablation; Address; Animals; Anti-Inflammatory Agents; Astrocytes; Behavioral; Biological Assay; Brain Pathology; CCR5 gene; CXCR4 gene; Cell surface; Cells; Data; Diagnosis; Disease; Eph Family Receptors; EphB2 Receptor; Ephrin B Receptor; Ephrin-B1; Ephrins; Excision; Family; Gene Expression; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interferon-beta; Interferons; Lead; Ligands; Light; Mediating; Mediator of activation protein; Messenger RNA; Microglia; Modeling; Mus; N-Methyl-D-Aspartate Receptors; Neurocognitive; Neurodegenerative Disorders; Neuronal Injury; Neurons; Pathology; Patients; Persons; Phenotype; Phosphorylation; Production; Proteins; RNA; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recombinant Interferon Beta; Recombinant Proteins; Research; Role; SIV; STAT3 gene; Signal Transduction; Speech; Stains; Structure; Surface; Synapses; Synaptic plasticity; Synaptophysin; Synaptosomes; System; Therapeutic; Transgenic Mice; Transgenic Organisms; Up-Regulation; Viral; Viral Proteins; Work; axon guidance; cytokine; gephyrin; glial activation; immune function; in vivo; in vivo Model; induced pluripotent stem cell; inflammatory marker; insight; knock-down; motor disorder; mouse model; nano-string; neuroAIDS; neuroinflammation; neuron development; neuroprotection; neurotoxicity; novel; prevent; protein expression; recruit; response; synaptic pruning

Project Abstract 37 million people worldwide are diagnosed with Human Immunodeficiency Virus (HIV). Of these 37 million, an estimated 15-55% of people living with HIV develop HIV-associated neurocognitive disorder (HAND). Previous work in ours and other labs identifies a transient increase of interferon beta (IFNβ), and antiviral type 1 interferon, preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and SIV models, suggesting a neuroprotective role for IFNβ in early HIV infection. We have previously shown that exogenous intranasal exposure of HIVgp120tg animals with IFNβ is sufficient to confer neuroprotection. Preliminary data from our lab describes the ability of HIVgp120 viral protein and IFNβ to regulate an important cell surface transmembrane ligand, ephrin-B1, in the CNS. Neuronal ephrin-B1 has been well studied and implicated in neuronal development, recruitment of NMDA receptors and synaptic plasticity mainly through its signaling with EphB receptors. However, ephrin-B1’s functional role in HIV, particularly microglial specific ephrin-B1, has not been well characterized at all. Our preliminary data identifies a statistically significant upregulation in EphB2 mRNA (one of the main receptors of ephrin-B1) in the cortex of HIV+ Patients with brain pathology. In addition, we describe significant inverse correlations between ephrin-B1 mRNA in the cortex of HIV+ Patients with both neurocognitive domain scores and inhibitory neuronal gene expression. In a transgenic NeuroHIV mouse in vivo model, we show in the cortex and hippocampus that the presence of gp120 upregulates ephrin-B1 protein expression in a cell-specific manner, including microglia. Treatment with IFNβ marginally reduces ephrin-B1 expression but significantly reduces ephrin-B1 off the surface of microglia. We believe that enhanced signaling between EphB2 and ephrin-B1 in the CNS of HIV+ Patients may lead to enhanced inflammatory response as well as unwanted synaptic pruning, and ablation of microglial ephrin-B1 will, in part, mitigate inflammation and synaptic pruning. This proposal seeks to identify the functional consequences of regulating microglial ephrin-B1 on microglial state and neuronal health in the context of HIV.

项目摘要