Maternal HIV: Developmental Neurotoxicity - Administrative Supplement

孕产妇艾滋病毒：发育神经毒性 - 行政补充

• 批准号: 9126896
• 负责人: Rosemarie M Booze
• 金额: $ 13.19万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126896
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Administrative Supplement; Adolescence; Adopted; Adult; Africa South of the Sahara; Age; Agonist; Animals; Behavior; Binding; Child; Childhood; Chronic; Chronic Disease; Cognition; Computer Simulation; Developed Countries; Developing Countries; Development; Diagnosis; Disease; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Failure; Functional disorder; Goals; HIV; HIV-1; Image; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Life; Longitudinal Studies; Mediating; Memory impairment; Microdialysis; Modeling; Morbidity - disease rate; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurologic; Pathology; Pathway interactions; Patients; Performance; Population; Process; Proteins; Quantitative Autoradiography; Rattus; Reporting; Research; Resources; Risk; Rodent; Role; Social Welfare; System; Techniques; Testing; Transgenes; Transgenic Organisms; Vertical Disease Transmission; Woman; antiretroviral therapy; brain tissue; clinically relevant; cost; developmental neurotoxicity; dopamine system; dopamine transporter; in vivo; longitudinal design; middle age; mortality; nervous system disorder; neurochemistry; neurocognitive disorder; neurotransmission; novel; pediatric human immunodeficiency virus; preclinical study; programs; prospective; radioligand; research study; success; uptake

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.

描述（由申请人提供）：虽然在美国，联合抗逆转录病毒疗法 (CART) 在减少母婴传播 (MTCT) 方面取得了巨大成功，但在全球范围内，MTCT 目前每天导致超过 1000 例新的 HIV-1 感染，或每两分钟超过 1 例新的儿科感染。最近对 HIV-1 感染患者进行的影像学、神经认知和尸检检查证明，多巴胺 (DA) 系统是一个临床相关靶标。使用前瞻性纵向设计，在这一竞争性更新中，我们将探讨这样一个假设：与 HIV-1 相关的神经认知功能障碍的发生和进展是 DA 系统（一个对炎症过程高度敏感的系统）病理学的结果和归因。纵向研究虽然在非啮齿类动物中具有挑战性，但对于系统地解决儿童 HIV-1/AIDS 问题至关重要，并且对于我们了解慢性 HIV-1 相关神经系统疾病 (HAND) 也至关重要。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生和进展。将在啮齿类动物断奶前、青春期、成年期和中年期间评估发育里程碑和一系列针对临床上已确定的表现神经认知功能障碍主要成分的行为的任务。 2) 确定主要 DA 受体亚型和 DA 转运蛋白的长期变化，作为慢性、低水平炎症和 HIV-1 蛋白暴露引起的神经认知功能障碍的候选神经化学机制。定量放射自显影将用于评估青春期、成年和中年期间 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生和进展中的完整性。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来治疗慢性、低水平炎症和 HIV-1 蛋白暴露引起的神经认知功能障碍。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，即使不介导 HIV-1 转基因的长期表达，也会导致神经认知损伤。该项目的目标是通过与儿科 HIV-1/AIDS 以及 HAND 相关的认知核心组成部分的转化模型来推进该领域的发展，更重要的是，识别（正常大鼠）和验证（特征更好的 HIV-1 转基因大鼠）新型神经治疗药物，以“调整”受 HIV-1 影响的认知领域。