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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的尽管进行了抗逆转录病毒治疗 (ART)，HIV 仍可导致认知和精神健康障碍，称为 HIV- 相关的神经认知障碍（HAND）。 HAND 病理学，其特征是突触树突损伤，类似于在衰老的大脑中观察到的损伤。目前，HAND 尚无有效治疗方法。在此外，有人认为抗逆转录病毒疗法（ART）会损害神经元功能；因此，确定可减少艾滋病毒介导的神经病理学的新机制非常重要。该项目的主要目标是发现艾滋病毒减少树突的生物学机制。我们的初步数据显示，艾滋病毒感染者的脑脊液（CSF）和死后大脑（PLWH），其神经认知功能降低，微管相关的含量较高蛋白 2 (MAP2)，与认知正常的 PLWH 相比。 MAP2 富含树突，与微管 (MT) 结合并在其形成和伸长中发挥关键作用，并帮助神经元贩运。然而，MAP2 具有不同的亚型，当在神经元中积累时，它们会促进损伤 MT 功能和树突变性。 HIV 可以直接改变 MAP2 水平或利用病毒蛋白来损害 MT 的功能。因为 HIV 介导的树突损失可以通过实验重现包膜糖蛋白 gp120，我们假设 HIV 通过 gp120-影响树突 MT 的整体功能依赖机制，包括改变 MAP2 与 MT 的结合。两个具体目标是建议检验这一假设。在目标 1 中，我们将研究 HIV/gp120 改变 MAP2 的机制。在目标 2 中，我们将使用各种方法来减少或增强 MAP2 同工型，并检查它们在树突损伤。更好地了解这些机制有助于药物开发以减少手的发生率。