HIV, HCV, and gender effects on Liver, Bone, and Vascular Health

项目摘要 我是一名受过传染病(ID)和艾滋病毒流行病学培训的医学教授，他制定了一种 国家认可的临床转化研究计划侧重于了解 人类免疫缺陷病毒和丙型肝炎病毒感染后脂肪组织的改变，代谢和炎症的紊乱，及其 对长期器官损伤(肝脏、骨骼和血管)的影响。我目前支持的研究包括：1)R01 这建立了一个纵向多点队列，约1500名感染艾滋病毒和/或丙型肝炎病毒的女性，以及那些 以确定艾滋病毒、丙型肝炎病毒和性腺老化对肝脏脂肪变性和纤维化的影响 使用FibroScan®的进展；2)第二个R01和默克调查员发起的奖项，审查 丙型肝炎病毒治愈的效果和：a)潜伏的艾滋病毒蓄积、免疫激活和肝纤维化；b)新的 接受直接作用抗病毒药物治疗的患者肾脏损伤的生物标志物；3)第二个默克奖 它检查了血浆整合酶链抑制物(INSTI)水平与身体成分的关系 变化；4)U01，其核心目标是研究美国男性和女性艾滋病毒的长期进展 来自多中心艾滋病队列研究(MACS)和妇女机构间艾滋病毒研究(WIHS)。我的 研究补助金利用WIHS的基础设施，WIHS在2019年成为MACS-WIHS的合并 队列研究(MWCCS)。对于K24更新所支持的新研究，我将增加我们目前的 从2020年开始将接受FibroScan®检查的女性样本和约3000名MWCCS男性样本：1)检查 与健康有关的差距(社会经济、行为和心理健康状况，即收入、教育、 居住地区/社区、医疗保健、食品安全和抑郁症)、生物性行为，包括 性腺老化和祖先信息标志影响脂肪变性和纤维化进展；2)调查 用OBJECT研究脂肪变性和纤维化进展的生物和免疫途径 测量内脏肥胖、性激素水平、肠道和口腔微生物组分析、血浆和头发 在MWCCS中获得的Insti水平；3)确定脂肪变性和纤维化如何影响肝外结局 (心脏、神经认知、骨骼)。建议的研究将扩大我的研究范围并扩大深度 我的辅导计划包括来自一系列新学科的学员(例如社会行为科学， 内分泌学、药理学和微生物学，以及ID、肝病和心脏病学的学员)， 和来自代表不足的少数群体(URM)的受教育者，他们可以有效地为艾滋病毒做出贡献 今天面临最大风险的社区。MWCCS为学员提供了访问丰富研究平台的便捷途径 在以患者为中心的研究中建立他们的职业生涯。我计划在专业和多样性方面进行额外的培训 领导力以及如何建立一个结构化和可持续的指导计划，以便及早和 从事艾滋病毒研究的职业中期调查人员(特别是URM调查人员)，并确保他们将 最终成为熟练的导师。

PROJECT ABSTRACT I am a Professor of Medicine trained in infectious diseases (ID) and HIV epidemiology, who has developed a nationally recognized clinical translational research program focused on understanding the associations of HIV and HCV infection with adipose tissue changes, and metabolic and inflammatory perturbations, and their effects on long-term organ injury (liver, bone, and vascular). My current supported research includes: 1) a R01 that establishes a longitudinal multisite cohort of ~1500 women with HIV and/or HCV infection, and those with neither infection to determine the effects of HIV, HCV, and gonadal aging on liver steatosis and fibrosis progression using FibroScan®; 2) a second R01 and a Merck investigator-initiated award that examines the effects of HCV cure and: a) latent HIV reservoirs, immune activation, and liver fibrosis and b) novel biomarkers of kidney injury in persons treated with direct acting antiviral agents; 3) a second Merck award that examines the association of plasma levels of integrase strand inhibitors (INSTIs) with body composition changes; and 4) a U01 whose core goal is to study the long-term progression of HIV in U.S. men and women from the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS). My research grants leverage the infrastructure of the WIHS, which in 2019 became the MACS-WIHS Combined Cohort Study (MWCCS). For the new research to be supported by the K24 renewal, I will augment our current sample of women with ~3000 MWCCS men who will undergo FibroScan® beginning in 2020 to: 1) examine how health-related disparities (socioeconomic, behavioral and mental health conditions, i.e. income, education, region/neighborhood of residence, healthcare access, food security, and depression), biologic sex including gonadal aging, and ancestry informative markers influence steatosis and fibrosis progression; 2) investigate the biologic and immune pathways associated with steatosis and fibrosis progression using objective measurement of visceral adiposity, sex hormone levels, gut and oral microbiome analysis, plasma and hair INSTI levels obtained in the MWCCS; 3) determine how steatosis and fibrosis affects extrahepatic outcomes (cardiac, neurocognition, bone). The proposed studies will expand my research portfolio and extend the depth of my mentoring program to include mentees from an array of new disciplines (e.g. socio-behavioral sciences, endocrinology, pharmacology, and microbiology, in addition to mentees in ID, hepatology, and cardiology), and mentees from underrepresented minority (URM) groups who can effectively contribute to the HIV communities most at risk today. The MWCCS provides mentees with ready access to a rich research platform to build their careers in patient-oriented research. I plan additional training in professional and diversity leadership and how to build a structured and sustainable mentoring program in order to develop early and mid-career investigators (especially URM investigators) in HIV research, and to ensure that they will ultimately become skilled mentors themselves.