IN UTERO EXPOSURE TO HAART

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。在怀孕期间使用高效抗逆转录病毒疗法（HAART）可大大降低新生儿感染艾滋病毒的发生率，并防止病毒的垂直传播。然而，安全性和对未感染儿童的健康和疾病风险的潜在长期影响仍然未知。最近，在妊娠期间使用HAART被证明在92%的非HIV感染的婴儿中显著增加线粒体毒性相关的血浆乳酸水平。另一项研究表明，在子宫内暴露于HAART的婴儿中，DNA突变的总体负担更高。此外，胎儿环境的改变可能对成年后的代谢和内分泌病理生理学产生长期影响（Barker假说），这一事实引起了对子宫暴露于HAART的长期安全性的担忧。成人动脉粥样硬化的进展被认为可能受到母体高胆固醇血症相关氧化应激的影响。我们实验室的长期目标是了解HAART相关代谢紊乱的病理生理机制。本研究的目的是确定宫内暴露于HAART的长期后果。基于HAART可诱导高脂血症以及HIV感染患者的氧化应激的事实，我们假设宫内暴露于HAART的婴儿在成年后患动脉粥样硬化的风险可能会增加，这是由于HAART相关的母亲氧化应激。我们将使用我们实验室目前开发的HAART相关血脂异常仓鼠模型来检验我们的假设。 重要性：对宫内暴露于HAART的儿童进行随访，以监测成人疾病（如动脉粥样硬化）的发作，将需要持续至少30-40年或更长时间的纵向研究。在这个快速发展的领域，时间是一个关键因素，不断有新的药物出现。因此，使用动物模型的研究是必要的，因为它们将提供1-2年内可比的长期毒性的见解，替代管理/预防策略，毒性较小的新药设计策略，可以提供指南和/或定义对宫内暴露于HAART的儿童/成人进行长期监测的需求。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Use of highly active antiretroviral therapy (HAART) during pregnancy dramatically reduces incidence of HIV infection among newborns and prevents vertical transmission of the virus. However, safety and potential long-term impact on health and disease risk among uninfected children remain unknown. Recently, use of HAART during pregnancy was demonstrated to significantly increase mitochondrial toxicity-associated plasma lactate levels among 92% of non HIV-infected infants. Another study indicated an overall higher burden of DNA mutations in infants exposed to HAART in utero. Moreover, the fact that alterations in fetal environment can have long-term consequences on metabolic and endocrine pathophysiology in adult life (Barker¿s Hypothesis) raises concern about long-term safety of uterine exposure to HAART. Progression of atherosclerosis in adult life is thought to be probably influenced by maternal hypercholesterolemia-associated oxidative stress. The long-term goal of our laboratory is to understand the pathophysiological mechanisms involved in HAART-associated metabolic disorders. The goal of this study is to determine the long-term consequences of inter-uterine exposure to HAART. Based on the fact that HAART can induce hyperlipidemia, as well as oxidative stress among HIV-infected patients, we hypothesize that infants exposed to HAART in utero may be at increased risk of atherosclerosis in adult life due to HAART-associated oxidative stress in mothers. We will test our hypothesis using a hamster model of HAART-associated dyslipidemia that has been currently developed in our laboratory. Significance: Follow up of children exposed to HAART in utero, for monitoring adult onset of diseases such as atherosclerosis will require longitudinal studies lasting at least 30-40 years or longer. Time is a critical factor in this fast evolving field, where newer drugs are constantly available. Therefore, studies using animal models are imperative, as they will provide insight into comparable long-term toxicities within 1-2 years, alternative management/preventive strategies, strategies for newer drug design that are less toxic and can provide guidelines and/or define the need for long-term surveillance of children/adults exposed to HAART in utero.