(PQ 6) New Models of KSHV Oncogenesis and KS Immune Environment

项目摘要 候选人和职业发展：Ayana Morales博士是一名传染病医生，致力于 在HIV相关恶性肿瘤领域的转化研究，以揭示病毒和宿主机制， 疾病，特别关注宿主与卡波西肉瘤疱疹病毒的相互作用， 感染她的首要目标是成为一名独立的医生科学家， 病毒和宿主的相互作用，最终发现新的生物标志物和更安全和改进的治疗方法。在 短期目标：1。扩大她在病毒学，免疫学和病理学方面的技术技能; 2。获得 有使用生物信息学的经验; 3.获得额外的赠款和手稿写作技能; 4.到 成功地竞争了K 08奖，以支持她过渡到职业生涯作为一个独立的研究人员。 研究：本研究计划作为R 01（PQ 6）KSHV致癌新模型的补充提出 KS Immune Environment，活动至2025年（PI Ethel Cesarman博士）。它建立在莫拉莱斯医生的发现上 原癌基因Wilms' tumor 1（WT 1）在卡波西肉瘤中高度表达，并且显着更高 在艾滋病病毒/艾滋病患者的KS病变中。Morales博士试图研究WT 1在KS中的作用，以及是否 HIV有助于WT 1介导的效应。具体来说，她将描述WT 1的空间关系， KS免疫肿瘤微环境（TME），并研究WT 1在2D和3D模型中的作用及其 免疫调节影响，以检验WT 1通过影响KS中的免疫逃避来促进KS中的免疫逃避的假设。 免疫细胞的运输和功能，这在HIV感染的存在下进一步受损。这将 通过以下具体目标实现：1）表征WT 1表达细胞的空间关系 2）应用二维电子显微镜观察WT 1在KSHV感染内皮细胞中的作用 和3D培养模型，以确定可能具有免疫调节后果的细胞内在效应。 意义：本研究将解剖WT 1在KS免疫环境中的空间关系， WT 1在KS的2D和3D模型中的作用，这可以更清楚地了解肿瘤免疫 微环境，并因此导致新的临床策略，以修复TME对KS。

Project Summary Candidate and career development: Dr. Ayana Morales is an Infectious Diseases physician committed to translational research in the field of HIV associated malignancies to uncover virus and host mechanisms of disease, with a specific focus on host interactions with Kaposi sarcoma herpesvirus in the context of HIV co- infection. Her overarching goal is to become an independent physician scientist investigating the questions of virus and host interaction to ultimately discover novel biomarkers and safer and improved treatments. In the short term, her goals are: 1. To expand her technical skills in virology, immunology, and pathology; 2. To gain experience in the use of bioinformatics; 3. Gain additional grant and manuscript writing skills; 4. To successfully compete for a K08 award to support her transition to a career as an independent researcher. Research: The research plan is proposed as a supplement to the R01 (PQ6) New Models of KSHV Oncogenesis and KS Immune Environment, active through 2025 (PI Dr. Ethel Cesarman). It builds upon Dr. Morales' findings that a proto-oncogene, Wilms' tumor 1 (WT1) is highly expressed in Kaposi sarcoma, and is significantly higher in KS lesions in people living with HIV/AIDS. Dr. Morales seeks to investigate the role of WT1 in KS and whether HIV contributes to WT1-mediated effects. Specifically, she will characterize the spatial relationship of WT1 to the KS immune tumor microenvironment (TME) and study the role of WT1 in 2D and 3D models and its immunomodulatory impacts to test the hypothesis that WT1 promotes immune evasion in KS by impacting immune cell trafficking and function, which are further compromised in the presence of HIV infection. This will be achieved through the following specific aims: 1) Characterize the spatial relationship of WT1-expressing cells to the KS immune TME, and 2) Investigate the role of WT1 in KSHV infected endothelial cells in vitro using 2D and 3D culture models to determine cell-intrinsic effects that can have immunomodulatory consequences. Significance: Our studies will dissect the spatial relationship of WT1 in the immune contexture of KS and the role of WT1 within 2D and 3D models of KS, which may provide a clearer understanding of the tumor immune microenvironment and hence lead to novel clinical strategies to recondition the TME against KS.