Maternal HIV: Developmental Neurotoxicity

孕产妇艾滋病毒：发育神经毒性

• 批准号: 6667903
• 负责人: Charles F. Mactutus
• 金额: $ 31.71万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667903
• 关键词: AIDS dementia complex; HIV envelope protein gp120; HIV infections; age difference; catecholamines; cognition disorders; developmental neurobiology; disease /disorder model; embryo /fetus toxicology; laboratory rat; neuroanatomy; neuropathology; neuropsychology; neurotoxicology; neurotoxins; pathologic process; perinatal; transcription factor; vertical transmission; virus protein

DESCRIPTION (provided by applicant): Vertical transmission (Mother to child) is the primary mode of HIV-1 infection among young children worldwide, resulting in at least 1700 new infections each day or more than one pediatric infection every minute (UNAIDS/WHO, 1999; 2001). Viral products released by HIV-infected cells cause widespread metabolic derangement as evident in neuronal dysfunction, disruption of neuro-glial relationships, and immune dysregulation, all of which ultimately cause cerebral dysfunction and precipitate the development of HIV dementia. It has been well established that specific proteins encoded by the HIV genome, e.g., Tat and gp120, 1) are neurotoxic, 2) are elevated in brain tissue of patients with HIV dementia, and 3) when presented to the brain in vivo, both proteins cause histological changes that are consistent with those seen in patients with HIV dementia. These data suggest that clinically relevant studies of HIV neuropathogenesis may now be performed in a rodent model. One notable advantage of directly studying the virotoxins is that neuropathogenesis may be studied independent of the virus per se and the complications of secondary infections. The proposed program specifically addresses the major question: What are the neurodevelopmental effects of the HIV proteins Tat and gp120 and how are these effects mediated? Our hypothesis is that: Neonatal exposure to the HIV proteins, Tat and gp120, will produce specific neurodevelopmental disruptions in cognitive processes and that these disruptions will be evident in central catecholamine systems and attributable to interference of key developmental processes. Using a virotoxin exposure model (HIV proteins Tat/gp120) our programmatic studies will determine the adverse effects of these proteins on the developing central nervous system of perinatal animals. Several very important pieces of information will be provided. First, we will identify dose-response functions for the adverse neurobehavioral and neuroanatomical effects of perinatal HIV protein neurotoxicity. Second, we will identify the potential critical periods responsible for the adverse neurobehavioral and neuroanatomical effects of perinatal HIV protein neurotoxicity. Third, these deleterious effects will be identified independent from those of secondary infections, polydrug and/or nutritional interactions that characterize the clinical HIV/AIDS populations. Thus, this project will: A) contribute to our understanding of Tat/gp120 in a clinically relevant rodent model, B) further provide a comprehensive examination of potential catecholamine targets responsible for early developmental disorders independent of secondary opportunistic infections, and C) provide the foundation for an examination of these very same potential mechanisms for HIV protein neurotoxicity in humans with the use of fetal autopsy tissue.

描述（由申请人提供）：垂直传播（母亲到儿童）是全球幼儿HIV-1感染的主要模式，每天至少导致1700个新感染或每分钟多种儿科感染（Unaids/Who，1999; 2001）。由HIV感染细胞释放的病毒产物会引起广泛的代谢危险，在神经元功能障碍，神经膜关系的破坏和免疫失调中显而易见，所有这些都最终引起大脑功能障碍并沉淀HIV痴呆症的发育。已经很好地确定，由HIV基因组编码的特异性蛋白质，例如Tat和Gp120，1）是神经毒性的，2）在HIV痴呆症患者的脑组织中升高，3）在体内呈现给脑的脑组织，这两种蛋白质会导致与HIV痴呆症患者相遇的组织学变化。这些数据表明，现在可以在啮齿动物模型中对HIV神经病发生的临床相关研究。直接研究病毒毒素的一个值得注意的优点是，可以研究神经病的发生本身与病毒本身和继发感染的并发症有关。拟议的程序专门解决了一个主要问题：HIV蛋白TAT和GP120的神经发育效应是什么？这些效应如何介导？我们的假设是：接触HIV蛋白TAT和GP120的新生儿暴露将在认知过程中产生特定的神经发育破坏，并且这些破坏在中央儿茶酚胺系统中将很明显，并且可归因于关键发育过程的干扰。使用病毒毒素暴露模型（HIV蛋白TAT/GP120）我们的程序化研究将确定这些蛋白质对发育中的中枢神经系统的不良反应。将提供几个非常重要的信息。首先，我们将确定围产期HIV HIV蛋白神经毒性的不良神经行为和神经解剖学作用的剂量反应功能。其次，我们将确定围产期HIV蛋白神经毒性的不良神经行为和神经解剖学作用的潜在关键时期。第三，这些有害作用将独立于临床HIV/艾滋病种群的继发性感染，聚发育和/或营养相互作用的鉴定。因此，该项目将：a）有助于我们在临床相关的啮齿动物模型中对TAT/GP120的理解，b）进一步提供了对潜在的儿茶酚胺靶标的全面检查，这些目标是导致早期发育障碍的靶标，而与继发机会感染无关，c）为HIV蛋白质神经毒性与Fettans的使用相同的潜在机制提供了基础。