Trajectories of socially regulated gene expression, methamphetamine use, and viral load among HIV-positive men who have sex with men (MSM) receiving contingency management

项目摘要 K 01导师研究科学家发展奖将为Michael Li博士提供宝贵的研究成果 经验，跨学科教师的指导培训，以及行为和行为相结合的培训活动 和基础科学，这将为他作为成瘾医学生物行为研究员的职业生涯做好准备 艾滋病毒治疗/预防。K 01机制将支持李博士的研究和培训工作， 在以下领域的专业知识：（1）神经调节的“压力”基因表达标记和成瘾的联系 （2）文化能力和道德行为;（3）技术分析和实质性 基因表达研究的分析方法;（4）临床试验方法;（5）专业发展。博士 李已经组建了一个跨学科的导师团队，他们将支持他的培训和研究的关键方面。 博士史蒂文·肖普托是成瘾医学领域一位富有成效和影响力的研究人员，他有一个 广泛的跟踪记录指导那些后来成为成功的独立研究人员的人。共同导师Dr. 史蒂文科尔是社会基因组学领域的先驱，他将指导李博士的转录组学方法培训。 博士杰西·克拉克将指导李博士进行临床试验操作和安全程序，托马斯贝林博士将 在临床试验中提供先进的统计方法和推理框架的广泛指导。李医生 提出研究神经调节的“压力”基因表达模式是否可以作为临床上的 甲基苯丙胺（METH）使用应急管理的有意义、非基于戒断的终点 艾滋病病毒感染者中的男性接触者的MUD。通过尿检确定的禁欲一直是唯一的标准 MUD治疗的临床结果，但提供了一个不完整的图片的患者恢复。基因表达 一种被称为逆境保守转录反应（CTRA）的模式可能提供了对这两种变化的深入了解。 社会心理健康和发病机制在MUD治疗过程中。CTRA的标志是 促炎基因的表达和I型干扰素基因的下调表达 消极的心理社会经历，如抑郁，焦虑和暴力，问题也与 使用冰毒。CTRA还涉及一些相同的基因调控途径，这些基因调控途径有助于METH相关的 发病机制，如涉及炎症和先天性抗病毒反应（与PLWH相关）。我 拟议的研究将使用两组临床试验设计（N=55），其中35名HIV阳性MSM接受MUD治疗 减少甲基苯丙胺的应急管理，以及20名符合非物质使用条件的艾滋病毒阳性男男性行为者 对照以实现以下目的：1）研究CTRA基因表达是否与METH一致 使用和病毒载量; 2）调查成瘾的社会心理指标是否与CTRA相关;以及 3)进行探索性试点调查，以确定CTRA介导相关性的程度 和病毒载量之间的联系总之，这个K 01研究项目和培训计划将发挥基础作用， 作为一名独立的药物使用和艾滋病毒研究人员，我早期的成功发挥了重要作用。

PROJECT ABSTRACT The K01 Mentored Research Scientist Development Award will provide Dr. Michael Li with invaluable research experience, mentored training from interdisciplinary faculty, and training activities in a combination of behavioral and basic sciences, which will prepare him well in his career as a biobehavioral researcher in addiction medicine and HIV treatment/prevention. This K01 mechanism will support Dr. Li’s research and training efforts to develop expertise in the following areas: (1) neurally regulated “stress” gene expression markers and links to addiction and HIV disease progression; (2) cultural competence and ethical conduct; (3) technical assay and substantive analytic methods in gene expression research; (4) clinical trial methods; and (5) professional development. Dr. Li has assembled an interdisciplinary mentorship team who will support key aspects of his training and research. Dr. Steven Shoptaw is a highly productive and influential researcher in addiction medicine, and he has an extensive track-record mentoring people who later became successful independent researchers. Co-mentor Dr. Steven Cole has pioneered the field of social genomics, and will direct Dr. Li’s training in transcriptomic methods. Dr. Jesse Clark will guide Dr. Li in clinical trial operations and safety procedures, and Dr. Thomas Belin will provide extensive mentoring in advanced statistical methods and inferential frameworks in clinical trials. Dr. Li proposes to investigate whether a neurally regulated “stress” gene expression pattern can serve as a clinically meaningful, non-abstinence-based endpoint for contingency management for methamphetamine (METH) use disorder (MUD) in MSM living with HIV. Abstinence determined by urine testing has been the only standard clinical outcome for MUD treatment, but provides an incomplete picture of patient recovery. The gene expression pattern called the conserved transcription response to adversity (CTRA) may provide insight into changes in both psychosocial health and pathogenesis over the course of MUD treatment. The CTRA is marked by upregulated expression of pro-inflammatory genes and downregulated expression of Type I interferon genes in response to negative psychosocial experiences such as depression, anxiety, and violence, problems also comorbid with METH use. The CTRA also involves some of same gene regulatory pathways that contribute to METH-related pathogenesis, such as those involving inflammation and innate antiviral responses (relevant to PLWH). My proposed research will use a two-arm clinical trial design (N=55) with 35 HIV-positive MSM with MUD receiving contingency management for METH reduction, and 20 HIV-positive MSM who qualify as a non-substance-using control to accomplish the following aims: 1) to investigate whether CTRA gene expression coincides with METH use and viral load; 2) to investigate whether psychosocial indicators of addiction are associated with CTRA; and 3) to conduct an exploratory pilot investigation to determine the degree to which CTRA mediates the association between METH use and viral load. Together, this K01 research project and training plan will play a fundamental role in my early success as an independent substance use and HIV researcher.