Metabolic Effects of In Utero Antiretrovirals on HIV Exposed Uninfected Infants

描述（由申请人提供）：本申请的主要目的是支持饶博士在hiv感染孕妇及其子女代谢并发症领域从一名受指导的研究员发展为一名独立研究者。候选人-职业目标和目标- Dr. ao设想自己是一名独立资助的研究人员，她将领导多学科团队设计、实施和分析感染艾滋病毒的孕妇和儿童的前瞻性研究，以评估子宫内艾滋病毒/抗逆转录病毒暴露后的各种长期健康结果。为了为今后的此类工作提供坚实的基础，在K奖期间，她计划获得开展和分析一项基于arv代谢并发症和胰岛素抵抗紊乱背后的科学原理的孕妇/婴儿双体前瞻性研究的充分经验。她拥有内科和儿科双重认证，非常适合研究这一队列。她曾在一家大型保健中心担任艾滋病毒服务主任，并参与哥伦比亚大学母婴传播倡议，这使她对国内和国际艾滋病毒母婴问题产生了兴趣。她最近在西奈山医学院（Mount Sinai School of Medicine， MSSM）获得了传染病研究金和公共卫生硕士学位。她还获得了竞争性资助，资助她在非洲和美国对感染艾滋病毒的孕妇进行研究。一年半前，她启动了一项试点研究，评估子宫内艾滋病毒的代谢并发症和感染艾滋病毒的未感染婴儿的抗逆转录病毒暴露，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，她的工作也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妊娠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与实施，2)纵向队列数据的统计分析，3)胰岛素抵抗代谢障碍，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，饶博士将参与四种类型的培训活动：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一个多学科专家小组(博士。伊莱恩·艾布拉姆斯，德里克·勒罗伊斯和罗达·斯珀林)以及曼哈顿邻近机构之间的高水平合作。环境- MSSM在研究、教育和临床服务方面开发了强大的项目，目前在NIH资助的医学院中排名前20位。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，医学部已经提供免费使用生物安全2级和冷冻设施来储存脐带血标本。此外，它还保证了Dr。

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. PUBLIC HEALTH RELEVANCE: This application will study the potential long-term metabolic effects of in utero exposure to HIV medications. It is relevant to public health because if metabolic complications such as diabetes are found in children exposed to HIV medications, this could impact current diabetes treatment and prevention strategies. Results of the study may show the need to screen these children for diabetes early in life as well as signal the need for additional considerations when choosing prenatal HIV medications.