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The ER-mitochondria interface in astrocytes during METH exposure and HIV-1 infection

METH 暴露和 HIV-1 感染期间星形胶质细胞中的 ER-线粒体界面

基本信息

批准号：
10259195
负责人：
Jessica Michelle Proulx
金额：
$ 3.5万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10259195
关键词：
ATF6 gene Academia Acute Affect Antioxidants Astrocytes Bioenergetics Biological Assay Biology Brain Calcium Cell physiology Cellular Stress Response Chronic Communication Coupling Development Endoplasmic Reticulum Ensure Exposure to Functional disorder Genus Hippocampus HIV HIV-associated neurocognitive disorder Health Health system Homeostasis Human Impairment Individual Infection Inositol Invaded Investigation Lipids Malondialdehyde Measures Mediating Mediator of activation protein Membrane Metabolic Methamphetamine Mitochondria Modeling Modification Molecular Morphology Nerve Degeneration Neuraxis Neurologic Neurons Organelles Pathogenesis Pathologic Pathology Pharmacology Phenotype Phosphotransferases Protein Kinase Proteins Public Health RNA RNA Interference Regulation Regulatory Pathway Research Research Project Grants Research Training Reticulum Risk Role Scheme Scientist Severities Signal Transduction Site Stimulus Stress Substance Use Disorder Testing Time Training Support Virion Virus Diseases Virus Replication arm base biological adaptation to stress blood-brain barrier permeabilization brain cell career comorbidity defined contribution endoplasmic reticulum stress excitotoxicity extracellular fitness inhibitor/antagonist insight methamphetamine abuse methamphetamine effect methamphetamine exposure methamphetamine use mitochondrial dysfunction neuroinflammation neuronal survival neuropathology neuroprotection neurotoxic neurotoxicity new therapeutic target novel overexpression prevent response therapeutic target vector

项目摘要

Astrocytes are key regulators of CNS health and neuronal function. Astrocyte mitochondrial dysfunction, such as induced by HIV-1 and METH, threatens the provision of essential metabolic and antioxidant support to neurons. Thus, delineating regulatory pathways that can be targeted to prevent aberrant mitochondria homeostasis in astrocytes will be imperative for ensuring neuronal fitness/survival against CNS pathologies. Direct contact sites between the endoplasmic reticulum (ER) and the mitochondria, termed mitochondrial associated membranes (MAMs), are central hubs for regulating several cellular processes required for homeostasis, including mitochondrial metabolic activity. In fact, the transfer of Ca2+ from the ER to mitochondria is essential for mitochondrial bioenergetics. Recent investigations have also identified unique, yet ill-defined contributions of the three unfolded protein response (UPR) arms in regulating MAM tethering and/or signaling. Briefly, protein kinase RNA-like endoplasmic reticulum kinase (PERK) has been determined as a key regulator for MAM tethering, inositol-requiring kinase 1 (IRE1α) is implicated in regulating MAM-mediated Ca2+ transfer, and activating transcription factor 6 (ATF6) is suspected to participate in MAM formation as it is known to mediate ER elongation and lipid homeostasis. However, these regulatory mechanisms have not yet been fully elucidated. Moreover, while modifications in MAM tethering and signaling have been involved in a number of neurodegenerative pathologies, their presence and participation in astrocyte biology remains to be determined. We hypothesize the ER-mitochondria interface is a key mediator of astrocyte mitochondrial dysfunction via Ca2+ and non-canonical UPR signaling during HIV-1 and METH pathogenesis. The proposed studies will examine changes in astrocyte mitochondrial function, UPR induction, Ca2+ signaling, and MAM formation in response to METH exposure and HIV-1 infection, followed by the delineation of ER-associated mechanisms regulating astrocyte mitochondrial function, and thus metabolic and antioxidant capacity. Aim 1 will evaluate how METH exposure and HIV-1 infection alter astrocyte metabolic and antioxidant capacity. Aim 2 will investigate how the ER-mitochondria interface regulates HIV-1/METH-mediated astrocyte mitochondrial dysfunction. Based on our preliminary findings, we propose to prioritize investigating the roles of PERK and IRE1α in regulating MAM tethering and MAM-mediated Ca2+ transfer, respectively, and how these functions alter astrocyte mitochondrial capacity. These studies will implement pharmacological inhibitors, specific silencing (si)RNAs and overexpression vectors to determine how UPR induction, Ca2+ signaling, and MAM tethering regulate astrocyte mitochondrial health during HIV-1/METH pathogenesis. These findings will help identify underlying mechanisms mediating astrocyte mitochondria dysfunction, which can be therapeutically targeted to optimize the metabolic and antioxidant coupling between astrocytes and neurons to promote neuronal survival during neurodegenerative pathologies.

星形胶质细胞是中枢神经系统健康和神经元功能的关键调节者。星形胶质细胞线粒体功能障碍，例如由HIV-1和冰毒诱导，威胁到向神经元。因此，描绘了可以靶向防止线粒体异常的调控途径星形胶质细胞的动态平衡对于确保神经元的健康/存活对抗中枢神经系统的病理是必不可少的。内质网(ER)与线粒体的直接接触部位称为线粒体相关膜(MAM)是调节几个细胞过程所需的中心枢纽动态平衡，包括线粒体代谢活动。事实上，钙离子从内质网到线粒体的转移对线粒体生物能量学来说是必不可少的。最近的调查也发现了独特的，但定义不明确的三个未折叠蛋白反应(UPR)臂在调节MAM系留和/或信号传递中的作用。简而言之，蛋白激酶rna样内质网激酶(Perk)已被确定为一种关键的调节因子。在巨噬细胞黏附分子系留过程中，肌醇需求激酶1(IRE1α)参与调节巨噬细胞黏附分子介导的钙离子转运，而激活转录因子6(ATF6)被怀疑参与了MAM的形成，因为它被认为是介导内质网延长与脂质动态平衡。然而，这些调控机制尚未完全阐明。此外，虽然对MAM系留和信令的修改涉及到许多神经退行性病变及其在星形胶质细胞生物学中的存在和参与仍有待确定。我们假设内质网-线粒体界面是星形胶质细胞线粒体功能障碍的关键介质在HIV-1和冰毒致病过程中，通过钙离子和非典型的UPR信号传导。拟议的研究将检查星形胶质细胞线粒体功能、UPR诱导、钙离子的变化响应冰毒暴露和HIV-1感染的信号和MAM的形成，然后描绘 ER相关机制调节星形胶质细胞线粒体功能，从而调节代谢和抗氧化剂容量。目标1将评估冰毒暴露和HIV-1感染如何改变星形胶质细胞代谢和抗氧化剂容量。目的2将研究内质网-线粒体界面如何调节HIV-1/METH介导的星形胶质细胞线粒体功能障碍。根据我们的初步调查结果，我们建议优先调查 PERK和IRE1α分别在调节MAM系留和MAM介导的钙离子转移中的作用功能改变了星形胶质细胞的线粒体能力。这些研究将实施药理抑制剂，特别是沉默(Si)RNA和过表达载体以确定UPR诱导、钙信号和MAM如何在HIV-1/METH致病过程中，拴系调节星形胶质细胞线粒体的健康。这些发现将会有所帮助确定介导星形胶质细胞线粒体功能障碍的潜在机制，这可以用于治疗旨在优化星形胶质细胞和神经元之间的代谢和抗氧化偶联，以促进神经元在神经退行性病变期间存活。