Maternal HIV: Developmental Neurotoxicity

描述（由申请人提供）：尽管联合抗逆转录病毒疗法（CART）在美国已经非常成功地减少了母婴传播（MTCT），但在全球范围内，MTCT目前每天导致1000例新的HIV-1感染，或者每两分钟就有1例以上的新的儿科感染。多巴胺（DA）系统是临床相关的靶点，最近的影像学、神经认知和HIV-1感染患者的尸检检查证明了这一点。使用前瞻性纵向设计，在这一竞争性更新中，我们将探索与HIV-1相关的神经认知功能障碍的发展和进展是由于DA系统的病理，这是一个对炎症过程高度敏感的系统。纵向研究虽然在非啮齿动物物种中具有挑战性，但对于系统地解决儿童HIV-1/AIDS至关重要，也是我们理解慢性HIV-1相关神经系统疾病（HAND）的基础。具体目的是：1)确定慢性、低水平炎症和HIV-1蛋白暴露导致的神经认知功能障碍的发生和进展。在啮齿动物断奶前、青春期、成年期和中年期间，将评估发育里程碑和一系列针对临床鉴定的神经认知功能障碍突出成分的行为的任务。2)确定慢性、低水平炎症和HIV- 1蛋白暴露导致的神经认知功能障碍的主要DA受体亚型和DA转运体的长期改变作为候选神经化学机制。定量放射自显影术将用于评估青春期、成年期和中年DA系统黑质纹状体和中皮质边缘通路中DA受体（D1、D2和D3）和DA转运体（DAT）的表达。3)确定慢性、低水平炎症和HIV-1蛋白暴露导致的神经认知功能障碍发生和进展中DAT功能的完整性。DAT功能将在慢性HIV-1蛋白暴露的转基因大鼠模型中使用体内NNF/微透析进行研究。4)确定慢性、低水平炎症和HIV-1蛋白暴露导致的神经认知功能障碍是否可以用目前使用的激动剂或拮抗剂或针对已识别的DA系统功能障碍的新型药物治疗。这些实验将确定DA受体和DAT的神经生物学变化的功能作用，作为一种神经化学机制，有助于（如果不是介导）HIV-1转基因慢性表达导致的神经认知障碍。该项目的目标是通过与儿童HIV-1/AIDS以及HAND相关的认知核心组件的翻译模型推进该领域，更重要的是，识别（正常大鼠）和验证（更好表征的HIV-1转基因大鼠）新的神经治疗方法来“调整”受HIV-1影响的认知领域。

DESCRIPTION (provided by applicant): Although combination antiretroviral therapy (CART) has been highly successful in reducing mother-to-child- transmission (MTCT) in the U.S., globally, MTCT is presently responsible for >1000 new HIV-1 infections each day or more than one new pediatric infection every two minutes. The dopamine (DA) system is a clinically relevant target as evidenced by recent imaging, neurocognitive, and post-mortem examinations of the HIV-1 infected patients. Using a prospective longitudinal design, in this competing renewal we will explore the hypothesis that the development and progression of neurocognitive dysfunction associated with HIV-1, is consequent of, and attributable to, pathology of the DA system, a system highly sensitive to inflammatory processes. Longitudinal studies, while challenging in non-rodent species, are critical for systematically addressing pediatric HIV-1/AIDS, and are also fundamental to our understanding of chronic HIV-1 associated neurological disorders (HAND). The specific aims are: 1) To determine the development and progression of neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV-1 protein exposure. Developmental milestones and an array of tasks directed at the behaviors expressing the prominent components of neurocognitive dysfunction that have been clinically identified will be assessed during the rodent preweaning period, adolescence, adulthood and middle age. 2) To determine the long-term alterations in the major DA receptor subtypes and DA transporter as a candidate neurochemical mechanism for the neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV- 1 protein exposure. Quantitative autoradiography will be used to assess the expression of DA receptors (D1, D2, and D3) and DA transporters (DAT) in the nigrostriatal and mesocorticolimbic pathways of the DA system during adolescence, adulthood and middle age. 3) To determine the integrity of DAT function in the development and progression of neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV-1 protein exposure. DAT function will be studied in a transgenic rat model of chronic HIV-1 protein exposure using in vivo NNF/microdialysis. 4) To determine whether the neurocognitive dysfunction consequent to chronic, low-level inflammation and HIV-1 protein exposure may be treated with currently used agonists or antagonists, or novel agents, targeted to the identified DA system dysfunction. These experiments will establish the functional role of the neurobiological changes in the DA receptors and DAT as a neurochemical mechanism contributing to, if not mediating, the neurocognitive impairments consequent to chronic expression of the HIV-1 transgene. The program goal is to advance the field with a translational model of the core components of cognition relevant to pediatric HIV-1/AIDS as well as to HAND, and more importantly, to identify (normal rats) and validate (the better characterized HIV-1 transgenic rat) novel neurotherapeutics to "tune" the cognition domains afflicted by HIV-1. PUBLIC HEALTH RELEVANCE: Despite the widely acknowledged success of antiretroviral therapy in reducing mother-to-child-transmission (MTCT) in the U.S., globally, MTCT is presently responsible for >1000 new HIV-1 infections each day or more than one new pediatric infection every two minutes (UNAIDS/WHO, 2010). We are uniquely poised to advance the field with a translational model of the core components of cognition relevant to pediatric HIV-1/AIDS as well as to HIV-1-associated neurocognitive disorders (HAND). Perhaps most importantly, our preclinical studies will identify (normal rats) and validate (the better characterized HIV-1 Tg rat novel neurotherapeutics to "tune" the cognition domains afflicted by HIV-1.