HIV promotes dendritic degeneration by altering microtubule-associated protein

HIV通过改变微管相关蛋白促进树突变性

• 批准号: 10618573
• 负责人: Italo Mocchetti
• 金额: $ 42.9万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618573
• 关键词: Acetylation; Acquired Immunodeficiency Syndrome; Adolescent; Affect; Aging; Automobile Driving; Autopsy; Binding; Biological; Brain; Brain Diseases; Central Nervous System Diseases; Cerebral cortex; Cerebrospinal Fluid; Cognitive; Cytoskeleton; Data; Dendrites; Event; Exhibits; Glycoproteins; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV-1; HIV-associated neurocognitive disorder; Human; Impaired cognition; Impairment; Incidence; Injury; Intermediate Filaments; Lead; Measures; Mediating; Mental Health; Mental disorders; Microfilaments; Microtubule Alteration; Microtubule-Associated Protein 2; Microtubule-Associated Proteins; Microtubules; Modification; Molecular; Nerve Degeneration; Neuraxis; Neurites; Neurocognitive; Neurons; Older Population; Pathology; Performance; Persons; Pharmaceutical Preparations; Play; Polymers; Post-Translational Protein Processing; Process; Protein Isoforms; Rattus; Reproducibility; Role; Stimulus; Synapses; Techniques; Testing; Tubulin; Viral Proteins; Virus; aged; aging brain; antagonist; antiretroviral therapy; drug development; effective therapy; env Gene Products; immune activation; innovation; knock-down; neuroAIDS; neuropathology; neurotoxic; neurotoxicity; novel marker; overexpression; prevent; protein aggregation; therapeutic target; trafficking

Abstract Despite antiretroviral therapy (ART), HIV can cause cognitive and mental health disorders, referred to as HIV- associated neurocognitive disorders (HAND). HAND pathology, which is characterized by synaptodendritic damage, resembles that observed in aging brain. At present, there are no effective treatments for HAND. In addition, it has been suggested that anti-retroviral therapy (ART) impairs neuronal function; thus, the identification of new mechanisms that can lead to a reduction of HIV-mediated neuropathology is important. The major goal of this project is to discover the biological mechanisms whereby HIV reduces dendrites. Our preliminary data show that the cerebrospinal fluid (CSF) and postmortem brains of people living with HIV (PLWH), whose neurocognitive performance is reduced, have a higher content of microtubule-associated protein 2 (MAP2), when compared to cognitively normal PLWH. MAP2, which is highly enriched in dendrites, binds to microtubules (MTs) and plays a key role in their formation and elongation, and helps neuronal trafficking. However, MAP2 has different isoforms that, when accumulate in neurons, they promote impairment of MTs function and dendritic degeneration. HIV could directly alter MAP2 levels or use viral proteins to impair the function of MTs. Because the HIV-mediated loss of dendrites is experimentally reproducible by the envelope glycoprotein gp120, we hypothesize that HIV affects the overall function of dendritic MTs by a gp120- dependent mechanism which encompasses an alteration of MAP2 binding to MTs. Two Specific Aims are proposed to test this hypothesis. In Aim 1, we will examine the mechanisms whereby HIV/gp120 alters MAP2. In Aim 2, we will use various approaches to reduce or enhance MAP2 isoforms and examine their role in dendritic injury. A better understanding of these mechanisms is instrumental for drug development to reduce the incidence of HAND.

摘要 尽管有抗逆转录病毒治疗（ART），艾滋病毒可导致认知和精神健康障碍，称为艾滋病毒- 相关的神经认知障碍（HAND）。HAND病理学，其特征在于突触树突 损伤，类似于在老化的大脑中观察到的。目前，HAND尚无有效的治疗方法。在 此外，已经提出抗逆转录病毒疗法（ART）损害神经元功能;因此， 鉴定可导致减少HIV介导的神经病理学的新机制是重要的。 该项目的主要目标是发现HIV减少树突的生物学机制。我们 初步数据显示，艾滋病毒感染者的脑脊液和死后大脑 （PLWH），其神经认知性能降低，具有较高的微管相关蛋白含量。 蛋白2（MAP 2），与认知正常PLWH相比。MAP 2在树突中高度富集， 与微管（MT）结合，在其形成和延伸中起关键作用，并帮助神经元 贩卖人口然而，MAP 2具有不同的亚型，当在神经元中积累时，它们促进损伤 MT功能和树突状细胞退化的证据。HIV可以直接改变MAP 2水平或利用病毒蛋白损害 MT的功能。因为HIV介导的树突缺失在实验上是可重复的， 包膜糖蛋白gp 120，我们假设HIV通过一个gp 120- 依赖性机制，其包括MAP 2与MT结合的改变。两个具体目标是 来检验这个假设。在目标1中，我们将研究HIV/gp 120改变MAP 2的机制。 在目标2中，我们将使用各种方法来减少或增强MAP 2亚型，并检查它们在以下方面的作用： 树突损伤更好地理解这些机制有助于药物开发， 手的发病率。