The role of TFAM alterations in HIV- and ART-induced mitochondrial dysfunction in the brain

TFAM 改变在 HIV 和 ART 诱导的大脑线粒体功能障碍中的作用

• 批准号: 10536678
• 负责人: Jerel Adam Fields
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536678
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Aging; Agonist; Anti-Inflammatory Agents; Area; Astrocytes; Autopsy; Basic Science; Behavioral Sciences; Bioenergetics; Biogenesis; Brain; Brain Diseases; Buffers; Chronic; Cognitive; Data; Disease; Excess Mortality; Exhibits; Exposure to; Extracellular Space; Gene Expression; Genetic; Glucose; Glutamine; Glycolysis; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-associated neurocognitive disorder; Homeostasis; Human; In Vitro; Infection; Inflammatory; Interleukins; Lactate Transporter; Learning; Link; Location; Memory; Metabolic; Metabolism; Microglia; Mitochondria; Mitochondrial Proteins; Mus; Neurodegenerative Disorders; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Oxidative Phosphorylation; Persons; Pharmaceutical Preparations; Phase; Phenotype; Play; Prevalence; Process; Production; Proteins; Quality of life; Reporting; Research; Research Priority; Role; Seminal; Specimen; Stimulus; Tenofovir; Testing; Therapeutic; Transgenic Mice; Viral; Viral Load result; Viral Proteins; Virus; Work; antiretroviral therapy; brain cell; brain tissue; cannabinoid receptor; comorbidity; comparison control; cytokine; in vitro Model; knock-down; mind control; mitochondrial dysfunction; monocyte; mortality risk; mouse model; neuroinflammation; neuronal metabolism; neuropathology; neurotoxic; neurotoxicity; neurotrophic factor; novel therapeutic intervention; prevent; release factor; transcription factor

SUMMARY Over 37 million people worldwide are infected with HIV and as many as 50% are affected by some form of neurological dysfunction. Despite effective antiretroviral therapy (ART), treatments to reduce the prevalence of HIV-associated neurocognitive disorder (HAND) are lacking. Recent findings suggest that increased mitochondrial activity in reactive astroglia play a causal role in mitochondrial dysfunction in neurons and this may be a targetable mechanism underlying neuronal dysfunction in virally suppressed people with HIV (PWH). Early during HIV infection, HIV-infected monocytes enter the brain and spread infection to resident microglia that then release HIV, HIV proteins, and inflammatory cytokines, all of which stimulate a proinflammatory phenotype in astroglia. Reactive astroglia are a hallmark of postmortem brain tissues from PWH with HAND even when on suppressive ART. Astroglia have many homeostatic functions, which are likely disrupted by chronic low-level HIV infection and long-term exposure to ART. One such function of astroglia is to buffer the concentrations of metabolic substrates (glucose, lactate, and glutamine) available to neurons in the extracellular space. Despite this crucial function to maintain bioenergetic homeostasis in the brain and the well-documented evidence of bioenergetic deficits during HAND, little is known about how these processes are affected in reactive astroglia. We’ve recently discovered that HIV and ART stimulate a switch in astroglia from being primarily glycolytic and secreting the byproduct lactate, to relying on oxidative phosphorylation to meet energy demands. To achieve this increase in mitochondrial activity, reactive astroglia increase levels of the mitochondrial biogenesis factors (TFAM), which is associated with a reduction in TFAM expression and viability in neurons. Importantly, this neurotoxicity is blocked by anti-inflammatory compounds that inhibit mitochondrial activity and reduce the reactive phenotype of reactive astroglia. However, the mechanistic link between increased mitochondrial activity in reactive astroglia and the reduction in mitochondrial biogenesis in neurons is not understood. We will investigate the role of astroglial metabolism in HAND by testing the hypothesis that increased mitochondrial activity in reactive astroglia compromises mitochondrial function in proximal neurons. AIM 1 will test in human brain cells how TFAM knockdown alters mitochondrial activity in and neurotoxicity conferred by reactive astroglia. AIM 2 will investigate in postmortem brain tissues from PWH with and without HAND and HIV- controls the location and changes in mitochondrial biogenesis and dynamics factors and lactate transporters in reactive astroglia and neurons. In AIM 3, mouse brains exposed to the HIV protein gp120 and ART drugs will be used to investigate mitochondrial biogenesis and dynamics factors and lactate transporters in astroglia and neurons. These AIMs address the Office of AIDS Research Priorities to 1) Address HIV-Associated Comorbidities; and 2) Advance Cross-Cutting Areas of research in the basic and behavioral sciences.

总结 全世界有超过3700万人感染艾滋病毒，多达50%的人受到某种形式的艾滋病的影响。 神经功能障碍尽管有有效的抗逆转录病毒疗法（ART），治疗，以减少患病率， 缺乏HIV相关的神经认知障碍（HAND）。最近的研究表明， 反应性星形胶质细胞中的线粒体活性在神经元中的线粒体功能障碍中起因果作用，这可能 在病毒抑制的HIV感染者（PWH）中，神经元功能障碍的潜在靶向机制。早期 在HIV感染期间，HIV感染的单核细胞进入大脑并将感染扩散到驻留的小胶质细胞， 释放HIV、HIV蛋白和炎性细胞因子，所有这些都刺激促炎表型， 星形胶质细胞。反应性星形胶质细胞是PWH伴HAND的死后脑组织的标志，即使在 星形胶质细胞具有许多稳态功能，这些功能可能被慢性低水平的 星形胶质细胞的功能之一是缓冲HIV感染和长期暴露于ART。 代谢底物（葡萄糖，乳酸盐和谷氨酰胺）可用于细胞外空间的神经元。尽管 这一维持大脑生物能量稳态的重要功能，以及有据可查的证据表明， 在HAND期间的生物能量缺陷，很少有人知道这些过程是如何在反应性星形胶质细胞的影响。 我们最近发现HIV和ART刺激星形胶质细胞从主要的糖酵解转变为 分泌副产物乳酸，依靠氧化磷酸化来满足能量需求。实现 这种线粒体活性的增加，反应性星形胶质细胞增加了线粒体生物合成因子的水平， （TFAM），其与神经元中TFAM表达和活力的降低相关。重要的是这 神经毒性被抗炎化合物阻断，抗炎化合物抑制线粒体活性并降低神经毒性。 反应性星形胶质细胞的反应性表型。然而，线粒体活性增加之间的机械联系 在反应性星形胶质细胞和减少线粒体生物合成的神经元是不清楚的。我们将 研究星形胶质细胞代谢在HAND中的作用， 反应性星形胶质细胞中的活性损害近端神经元中的线粒体功能。AIM 1将在 脑细胞中TFAM敲低如何改变线粒体活性和反应性神经毒性 星形胶质细胞。AIM 2将在PWH（有和没有HAND）和HIV对照的死后脑组织中进行研究 线粒体生物合成和动力学因子及乳酸转运蛋白在反应性心肌细胞中的定位和变化 星形胶质细胞和神经元。在AIM 3中，暴露于HIV蛋白gp 120和ART药物的小鼠大脑将被用于 研究星形胶质细胞和神经元中线粒体生物发生和动力学因子以及乳酸转运体。 这些AIM针对艾滋病研究优先事项办公室，以1）解决艾滋病毒相关的合并症;以及2） 推进基础科学和行为科学研究的交叉领域。