Cocaine and HIV Influence Mitochondrial Epigenetics in Astrocytic Networks

可卡因和艾滋病毒影响星形细胞网络中的线粒体表观遗传学

基本信息

批准号：
10219215
负责人：
Samikkannu Thangavel
金额：
$ 48.19万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219215
关键词：
5&apos -AMP-activated protein kinase Acquired Immunodeficiency Syndrome Address Affect Apoptosis Astrocytes Axon Biogenesis Brain Buffers Cell physiology Cells Central Nervous System Diseases Clinical Cocaine Cocaine Abuse Cocaine Users Conditioned Culture Media Cytochrome c Reductase DNA Methylation Dendrites Deterioration Development Dioxygenases Energy Metabolism Energy Supply Energy Transfer Energy-Generating Resources Enhancers Enzymes Epigenetic Process Family Functional disorder Gene Expression Gene Proteins Generations Glutamates HIV HIV Infections HIV Transactivator Protein HIV-1 Hydroxyl Radical Impairment In Vitro Infection Lead Mediating Metabolic Metabolism Microglia Mitochondria Mitochondrial DNA Mus NADH Neuraxis Neuronal Dysfunction Neuronal Plasticity Neurons Neuropathogenesis Neuroprotective Agents Oligodendroglia Oxidative Phosphorylation Oxidative Stress Oxidoreductase PPAR gamma Play Post-Translational Protein Processing Potassium Production Research Resources Risk Factors Role Serine Sucrose Switching Complex Therapeutic Toxin Transferase Transgenic Mice Vertebral column Viral axon growth brain metabolism cell growth cocaine exposure cocaine use density extracellular in vivo mitochondrial genome mouse model neuron loss neuronal growth neuronal survival neurotoxicity neurotrophic factor preservation sensor targeted treatment therapeutic target

项目摘要

Project Summary/Abstract Astrocytes are the major regulators for energy storage, utilization and metabolic function in the central nervous system (CNS). Cocaine abuse and HIV infections are significant risk factors for disrupting brain energy metabolism and cocaine abuse is strongly associated with HIV-1 infection and a subsequent development of AIDS. The proposed research is aimed at investigating the effects of cocaine and HIV-Transactivator protein (HIV-Tat) on astrocyte energy metabolism and associated neuronal impairments. Altered DNA methylation in the region of the mitochondrial genome encoding the NADH dehydrogenase (NDH- displacement loop (D-loop) Family) subunits (ND1-ND6) plays a critical role in energy storage and utilization by regulating the energy source of brain metabolism to preserve CNS cell functions. Therefore, we investigated the role of cocaine and/or HIV-1 infection on the mitochondrial epigenetic mechanisms that alters the astrocytic energy metabolism. Moreover, the role of mitochondrial DNA methyl transferases (mtDNMTs) in impacting energy deficits in astrocytes leading to neuronal impairment has never been elucidated in the context of either cocaine or HIV-Tat, or in combination. Our preliminary studies showed that cocaine and/or HIV-1 Tat targets DNMTs and mtDNMTs (mtDNMT1, mtDNMT3A and mtDNMT3B) with concomitant activation of mitochondrial biogenesis in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) that is known to regulate mtDNA synthesis and control energy metabolism affecting neuro plasticity and spine density. We thus hypothesize that cocaine acts as a co-factor in the neuropathogenesis of HIV-Tat by activating DNMTs expression in astrocytes leading to energy deficits and impacting DNA methylation and mitochondrial biogenesis. These epigenetic mechanisms are mediated by of 5-methylcytosine (5-mC), 5-hydroxymethylcytosine (5hmC) the regulatory D-loop region and its effect and ten-eleven translocation (TET) family dioxygenases , which affect energy transfer into neurons and dysregulate neuro plasticity, spine density and cell growth. Accordingly, in the specific Aim # 1A we will examine whether cocaine in association with HIV-Tat affect energy dysfunction of astrocytes and impacts DNMTs, mtDNMTs and biogenesis-led energy transfer, in Aim 1B# we propose to determine the effect on neuroplasticity/ axons/ dendrites formation and cell growth in primary neurons thereby contributing to neuronal death; the specific Aim # 2, we will validate the mechanistic study involving cocaine exposure of HIV-Tat (GT-tg) transgenic mice to investigate the mtDNMTs role in energy metabolism, and whether piracetam (a neuro-protective agent) treatment reverses the effects of cocaine and HIV-Tat on mtDNMTs leading to neuro plasticity and axons/ dendrites formation to develop a therapeutic strategy regulating energy metabolism impacting neurotoxicity. An understanding of cocaine and HIV-associated astrocytes energy deficits that lead to neurotoxicity will have translational significance for therapeutic targeting and controlling the energy metabolism in HIV-infected cocaine users.

项目概要/摘要星形胶质细胞是中枢神经系统能量储存、利用和代谢功能的主要调节者可卡因滥用和艾滋病毒感染是破坏大脑能量的重要危险因素。新陈代谢和可卡因滥用与 HIV-1 感染以及随后的发展密切相关艾滋病。拟议的研究旨在调查可卡因和艾滋病毒反式激活蛋白的影响。 (HIV-Tat) 对星形胶质细胞能量代谢和相关神经元损伤的影响。线粒体基因组中编码 NADH 脱氢酶（NDH- 位移环（D 环） Family）亚基（ND1-ND6）通过调节能量在能量储存和利用中发挥着关键作用因此，我们研究了可卡因的作用。和/或 HIV-1 感染对改变星形胶质细胞能量的线粒体表观遗传机制的影响此外，线粒体 DNA 甲基转移酶 (mtDNMT) 在影响能量方面的作用。在可卡因的背景下，星形胶质细胞的缺陷导致神经元损伤从未得到阐明或 HIV-Tat，或组合我们的初步研究表明可卡因和/或 HIV-1 Tat 靶向 DNMT。和 mtDNMT（mtDNMT1、mtDNMT3A 和 mtDNMT3B），同时激活线粒体过氧化物酶体增殖物激活受体 γ 共激活剂 1-α (PGC-1α) 的生物发生，已知调节 mtDNA 合成并控制影响神经可塑性和脊柱密度的能量代谢。可卡因通过激活 DNMT 作为 HIV-Tat 神经发病机制的辅助因子星形胶质细胞中的表达导致能量不足并影响 DNA 甲基化和线粒体这些表观遗传机制是由生物发生机制介导的。的 5-甲基胞嘧啶 (5-mC)、5-羟甲基胞嘧啶 (5hmC) 调节D环区域及其作用和 10-11 易位 (TET) 家族双加氧酶，影响能量转移到神经元并失调神经可塑性、脊柱密度因此，在具体目标#1A中，我们将检查可卡因是否与细胞生长有关。 HIV-Tat 影响星形胶质细胞的能量功能障碍并影响 DNMT、mtDNMT 和生物发生主导的能量转移，在目标 1B# 中，我们建议确定对神经可塑性/轴突/树突形成和细胞的影响原代神经元的生长从而导致神经元死亡；具体目标#2，我们将验证涉及 HIV-Tat (GT-tg) 转基因小鼠可卡因暴露的机制研究，以研究 mtDNMT 在能量代谢中的作用，以及吡拉西坦（a 神经保护剂）治疗可逆转以下效果 mtDNMT 上的可卡因和 HIV-Tat 导致神经可塑性和轴突/树突形成，从而开发调节能量代谢影响神经毒性的治疗策略。导致神经毒性的 HIV 相关星形胶质细胞能量缺陷将对以下疾病具有转化意义：治疗目标和控制感染艾滋病毒的可卡因使用者的能量代谢。