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）在减少美国母婴传播（MTCT）方面非常成功，在全球范围内，母婴传播目前每天造成超过1000例新的HIV-1感染，或每两分钟造成一例以上的新的儿科感染。多巴胺（DA）系统是一个临床相关的目标，证明了最近的成像，神经认知，和死后检查的HIV-1感染的患者。使用前瞻性纵向设计，在这种竞争性更新，我们将探讨的假设，即与HIV-1相关的神经认知功能障碍的发展和进展，是由于，并归因于，病理的DA系统，系统高度敏感的炎症过程。纵向研究，而在非啮齿类动物物种的挑战，是系统地解决儿科HIV-1/艾滋病的关键，也是我们的慢性HIV-1相关的神经系统疾病（手）的理解的基础。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。将在啮齿动物断奶前、青春期、成年期和中年期间评估发育里程碑和一系列针对表达临床上已确定的神经认知功能障碍的主要成分的行为的任务。2)确定主要DA受体亚型和DA转运蛋白的长期改变，作为慢性、低水平炎症和HIV- 1蛋白暴露导致神经认知功能障碍的候选神经化学机制。将使用定量放射自显影术评估青春期、成年期和中年期间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转运蛋白（DAT）的表达。3)确定DAT功能在慢性、低水平炎症和HIV-1蛋白暴露导致的神经认知功能障碍的发展和进展中的完整性。将使用体内NNF/微透析在慢性HIV-1蛋白暴露的转基因大鼠模型中研究DAT功能。4)确定慢性、低水平炎症和HIV-1蛋白暴露引起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确定的DA系统功能障碍的新型药物治疗。这些实验将确立DA受体和DAT的神经生物学变化作为神经化学机制的功能作用，该神经化学机制促成（如果不是介导的话）HIV-1转基因的慢性表达所导致的神经认知障碍。该计划的目标是推进该领域的认知相关的儿科HIV-1/艾滋病以及手的核心组成部分的翻译模型，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折磨的认知领域。 公共卫生相关性：尽管抗逆转录病毒疗法在减少美国母婴传播（MTCT）方面取得了广泛认可的成功，目前，在全球范围内，母婴传播每天造成1 000多例新的艾滋病毒1型感染，或每两分钟造成1例以上新的儿科感染（艾滋病规划署/世卫组织，2010年）。我们正以独特的姿态推进这一领域的认知核心组成部分的翻译模型，与儿科HIV-1/AIDS以及HIV-1相关的神经认知障碍（HAND）相关。也许最重要的是，我们的临床前研究将确定（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折磨的认知领域。

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.