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: 10403383
• 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/10403383
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Aging; Agonist; Anti-Inflammatory Agents; Area; Astrocytes; Autopsy; Basic Behavioral Science; 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 therapy; HIV-associated neurocognitive disorder; Homeostasis; Human; In Vitro; Infection; Inflammatory; Interleukins; Lactate Transporter; Lead; Learning; Link; Location; 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 Proteins; Virus; Work; antiretroviral therapy; brain cell; brain tissue; cannabinoid receptor; comorbidity; cytokine; in vitro Model; knock-down; mind control; mitochondrial dysfunction; monocyte; mortality risk; mouse model; neuroinflammation; neuronal metabolism; neurotoxic; neurotoxicity; 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.

概括 全球有超过 3700 万人感染艾滋病毒，其中多达 50% 的人受到某种形式的影响 神经功能障碍。尽管抗逆转录病毒疗法（ART）有效，但降低患病率的治疗方法 缺乏 HIV 相关神经认知障碍 (HAND)。最近的研究结果表明，增加 反应性星形胶质细胞中的线粒体活性在神经元线粒体功能障碍中发挥因果作用，这可能 是病毒抑制的艾滋病毒感染者（PWH）神经元功能障碍的潜在机制。早期的 在艾滋病毒感染期间，感染艾滋病毒的单核细胞进入大脑并将感染传播到驻留的小胶质细胞，然后 释放 HIV、HIV 蛋白和炎性细胞因子，所有这些都会刺激促炎表型 星形胶质细胞。即使在使用 HAND 的情况下，反应性星形胶质细胞也是 PWH 死后脑组织的一个标志 抑制性艺术。星形胶质细胞具有许多稳态功能，这些功能可能会受到长期低水平的干扰 HIV 感染和长期接触 ART。星形胶质细胞的其中一项功能是缓冲 细胞外空间神经元可利用的代谢底物（葡萄糖、乳酸和谷氨酰胺）。尽管 这一维持大脑生物能稳态的重要功能以及有据可查的证据 尽管 HAND 期间存在生物能量缺陷，但人们对这些过程如何在反应性星形胶质细胞中受到影响知之甚少。 我们最近发现 HIV 和 ART 刺激星形胶质细胞从主要糖酵解和 分泌副产物乳酸，依靠氧化磷酸化来满足能量需求。达到 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)，与神经元中 TFAM 表达和活力的减少有关。重要的是，这 神经毒性被抗炎化合物所阻断，这些化合物抑制线粒体活性并减少 反应性星形胶质细胞的反应表型。然而，线粒体活性增加之间的机制联系 反应性星形胶质细胞中的作用和神经元线粒体生物发生的减少尚不清楚。我们将 通过检验线粒体增加的假设，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的活动会损害近端神经元的线粒体功能。 AIM 1 将在 人脑细胞 TFAM 敲低如何改变线粒体活性和反应性赋予的神经毒性 星形胶质细胞。 AIM 2 将在有或没有 HAND 和 HIV 对照的情况下对来自 PWH 的死后脑组织进行研究 反应中线粒体生物发生和动力学因素以及乳酸转运蛋白的位置和变化 星形胶质细胞和神经元。在 AIM 3 中，暴露于 HIV 蛋白 gp120 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的线粒体生物发生和动力学因素以及乳酸转运蛋白。 这些目标明确了艾滋病研究办公室的优先事项： 1) 解决与艾滋病毒相关的合并症；和 2) 推进基础科学和行为科学的交叉研究领域。