Metabolic Effects of In Utero Antiretrovirals on HIV Exposed Uninfected Infants

描述(申请人提供)：本申请的主要目标是支持Jao博士在感染艾滋病毒的孕妇及其子女的代谢并发症领域从一名指导研究员发展为一名独立调查员。候选人-职业目标和目的-Jao博士设想自己是一名独立资助的研究人员，将领导多学科团队设计、实施和分析针对感染艾滋病毒的孕妇和儿童的前瞻性研究，以评估在宫内接触HIV/ARV后的各种长期健康结果。为了为今后的这类工作奠定坚实的基础，在K奖期间，她计划获得全面的经验，对孕妇/婴儿二联体进行前瞻性研究，该研究基于ARV代谢并发症和胰岛素抵抗障碍背后的科学原理。拥有内科和儿科双重认证的她非常适合研究这一群体。她在一家大型保健中心担任艾滋病毒服务主任的经历以及在哥伦比亚大学母婴传播(MTCT-Plus)倡议中的经历塑造了她对国内和国际艾滋病毒母婴问题的兴趣。她最近在西奈山医学院(MSSM)完成了传染病研究员和公共卫生硕士学位。她还获得了竞争性赠款，以资助她在非洲和美国感染艾滋病毒的孕妇的研究。一年半前，她启动了一项试验性研究，评估暴露在艾滋病毒感染中的未感染婴儿在宫内的代谢并发症，这是她目前K奖研究提案的基础。她预计，从这项研究和K奖提案中获得的知识将开始建立纵向跟踪这一关键队列所需的基础设施。她预计，她的工作还可能指导有兴趣将这一领域的研究转移到国际上的研究人员，并在全球范围内解决有关怀孕期间使用抗逆转录病毒药物长期安全性的问题时，为政策提供信息。职业培训/发展计划--拟议的培训计划包括4个不同的模块：1)艾滋病毒母婴队列研究的设计和实施，2)纵向队列数据的统计分析，3)胰岛素抵抗代谢紊乱，以及4)艾滋病毒感染孕妇及其子女的管理。为了发展每个模块的专业知识，Jao博士将参与4种类型的培训活动：1)指导，2)课程作业，3)会议/研究研讨会，4)临床培训。她独特的指导结构利用了多学科专家小组(Elaine Abrams博士、Derek LeRoith博士和Rhoda Sperling博士)以及曼哈顿邻近机构之间的高度合作。环境-MSSM在研究、教育和临床服务方面发展了强大的项目，目前已跻身NIH资助的前20所医学院之列。因此，它将为完成她拟议的研究提供所需的实际支持。在试点研究中，医学部已经提供了免费使用生物安全二级和冰柜设施来储存脐带血样本。此外，它还保证了Dr。 JAO 75%保护了研究时间。产科和儿科通过临床工作人员和教职员工提供支持，他们成功地合作了这个K23奖的试点项目。西奈山临床研究中心(CRC)将在K奖期间继续提供护理和生物信息学支持，该中心正在进行试点研究的第三次礼仪密集访问。最后，莫兰博士的实验室将继续为研究中的脂肪因子和细胞因子测试提供支持。研究-这项研究调查了宫内HIV和ARV暴露对与胰岛素抵抗相关的婴儿代谢紊乱的影响。它结合了艾滋病毒、产科、儿科、内分泌学和免疫学领域的专家导师和合作者，以解决有关宫内艾滋病毒和抗逆转录病毒感染对代谢影响的知识空白。其具体目的是：1)评估宫内HIV和ARV暴露是否与出生第一年的胰岛素抵抗有关；2)评估涉及已知的胰岛素抵抗危险因素的间接途径和涉及炎症的直接途径是否在与宫内HIV和ARV暴露相关的胰岛素抵抗中发挥作用。在2009年开始的一项试点研究的基础上，将在西奈山医院进行一项关于怀孕、感染艾滋病毒和未感染母婴的前瞻性队列研究。主要终点将是12个月大时胰岛素抵抗的稳态模型评估(HOMA-IR)测量。关键的产前数据将包括病史和抗逆转录病毒史以及艾滋病毒感染的措施。分娩时收集的数据将包括出生体重和结局，以及脐带血中特定脂肪因子和细胞因子的数据。收集的关键出生后数据将包括出生第一年的生长模式和HOMA-IR。这项研究将扩大我们对宫内HIV和ARV暴露的早期代谢影响的理解。如果在生命早期发现存在不利的代谢影响，这可能会潜在地影响目前的儿科糖尿病预防和治疗策略。此外，未来的研究对于区分哪些抗逆转录病毒药物对感染艾滋病毒的妇女及其后代来说可能是或可能不是更安全的方案将是至关重要的。

DESCRIPTION (provided by applicant): The primary objective of this application is to support Dr. Jao's career development from a mentored researcher to an independent investigator in the field of metabolic complications in HIV-infected pregnant women and their children. Candidate - Career Goals and Objectives - Dr. Jao envisions herself as an independently funded researcher who will lead multi-disciplinary teams in designing, implementing, and analyzing prospective studies of HIV-infected pregnant women and children to evaluate a variety of long term health outcomes following in utero HIV/ARV exposures. In order to provide a strong foundation for future work of this kind, during the K Award, she plans to gain the full experience of conducting and analyzing a prospective study of pregnant women/infant dyads which is grounded in the scientific rationale behind metabolic complications of ARVs and disorders of insulin resistance. Dual-certified in internal medicine and pediatrics, she is well-suited to study this cohort. Her experience as the Director of HIV Services at a large health center and with the Mother-To-Child-Transmission (MTCT-Plus) Initiative of Columbia University has shaped her interest in HIV maternal-child issues domestically and internationally. She recently completed a fellowship in Infectious Diseases and a Master of Public Health degree at Mount Sinai School of Medicine (MSSM). She has also obtained competitive grants to fund her research in HIV-infected pregnant women both in Africa and the U.S. A year and half ago she launched a pilot study evaluating metabolic complications of in utero HIV and ARV exposure in HIV-exposed uninfected infants which is the basis of her current K Award research proposal. She anticipates that knowledge gained from this study and that of the K Award proposal will begin to establish the infrastructure needed to follow this key cohort longitudinally. She anticipates that her work may also direct investigators interested in transposing research in this field internationally and inform policy as questions regarding the long-term safety of ARVs administered in pregnancy are addressed globally. Career Training/Development Plan - The proposed training plan consists of 4 distinct modules: 1) HIV Maternal/ Child Cohort Study Design and Implementation, 2) Statistical Analysis of Longitudinal Cohort Data, 3) Metabolic Disorders of Insulin Resistance, and 4) Management of HIV-infected Pregnant Women and their Children. To develop expertise in each module, Dr. Jao will engage in 4 types of training activities: 1) Mentoring, 2) Coursework, 3) Conferences/ Research Seminars, and 4) Clinical Training. Her unique mentoring structure capitalizes on a multi-disciplinary panel of experts (Drs. Elaine Abrams, Derek LeRoith, and Rhoda Sperling) and the high levels of collaboration among neighboring institutions in Manhattan. Environment - MSSM has developed strong programs in research, education, and clinical services and is now ranked in the top 20 medical schools for NIH funding. As such, it will provide the practical backing needed to complete her proposed study. The Department of Medicine has already provided free use of a Biosafety Level 2 and freezer facility for storage of cord blood specimens in the pilot study. In addition, it has guaranteed Dr. Jao 75% protected research time. The Departments of Obstetrics and Pediatrics have provided their support through clinic staff and faculty who have collaborated successfully on the pilot project of this K23 Award. The Mount Sinai Clinical Research Centers (CRC) where the protocol-intensive 3rd visit of the pilot study is being carried out will continue to provide nursig and bioinformatics support during the K Award. Lastly, Dr. Moran's laboratory will continue to provide support for adipokine and cytokine testing in the study. Research - This study investigates the impact of in utero HIV and ARV exposure on infant metabolic disorders associated with insulin resistance. It combines expert mentors and collaborators in the fields of HIV, obstetrics, pediatrics, endocrinology, and immunology in order to address gaps in knowledge concerning the metabolic effects of in utero HIV and ARV exposure. The specific aims are: 1) to assess whether in utero HIV and ARV exposure is associated with insulin resistance in the first year of life, and 2) to assess whether indirect pathways involving known risk factors for insulin resistance and direct pathways involving inflammation play a role in insulin resistance associated with in utero HIV and ARV exposure. Building on a pilot study begun in 2009, a prospective cohort study of pregnant HIV-infected and -uninfected mother/child dyads will be conducted at Mount Sinai Hospital. The primary endpoint will be the Homeostatic Model Assessment (HOMA- IR) measurement of insulin resistance at 12 months of age. Key prenatal data will include medical and ARV history and measures of HIV infection. Data collected at delivery will include birth weight and outcomes as well as cord blood for specific adipokines and cytokines. Key postnatal data collected will consist of growth patterns in the first year of life and HOMA-IR. This study will expand our understanding of the early metabolic effects of in utero HIV and ARV exposure. If adverse metabolic effects are found to be present early in life, this may potentially impact current pediatric diabetes prevention and treatment strategies. Moreover, future studies would be crucial in distinguishing which ARVs may or may not represent a safer regimen for both the HIV- infected woman and her offspring.