Maternal HIV: Developmental Neurotoxicity - Administrative Supplement

描述(申请人提供)：尽管联合抗逆转录病毒疗法(CART)在减少美国的母婴传播(MTCT)方面取得了巨大成功，但在全球范围内，MTCT目前每天导致1000例新的HIV-1感染，或每两分钟超过一例儿科感染。多巴胺(DA)系统是一个临床相关的靶点，最近对HIV-1感染患者进行的成像、神经认知和尸检证明了这一点。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DA系统病理的结果和归因，DA系统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科艾滋病毒-1/艾滋病至关重要，也是我们理解慢性艾滋病毒-1相关神经疾病(HAND)的基础。具体目标是：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展和进展。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任务，这些任务针对的是表现出临床上已确定的神经认知功能障碍的显著组成部分的行为。2)研究慢性低水平炎症和HIV-1蛋白暴露所致神经认知功能障碍的神经化学机制，探讨DA受体亚型和DA转运体的长期变化。定量放射自显影将被用来评估在青春期、成年期和中年期间DA系统的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DAT功能在慢性低水平炎症和HIV-1蛋白暴露所致神经认知功能障碍的发生和发展中的完整性。DAT功能将在转基因大鼠的慢性HIV-1蛋白暴露模型中使用体内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新的药物来治疗，这些药物针对已发现的DA系统功能障碍。这些实验将确定DA受体和DAT中神经生物学变化的功能作用，作为一种神经化学机制，即使不是调节，也是促成HIV-1转基因慢性表达所导致的神经认知障碍。该计划的目标是通过与儿童HIV-1/AIDS以及与手相关的认知核心成分的翻译模型来推动该领域的发展，更重要的是，识别(正常大鼠)和验证(更好地表征HIV-1转基因大鼠)新的神经疗法，以“调整”受HIV-1影响的认知域。

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.