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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.

项目总结/文摘