(PQ6) Mesenchymal stem cell based and immunocompetent mouse models of HIV/AIDS KSHV-driven sarcomagenesis

(PQ6) 基于间充质干细胞和免疫活性的 HIV/AIDS 小鼠模型 KSHV 驱动的肉瘤发生

• 批准号: 10609000
• 负责人: Sabita Roy
• 金额: $ 59.93万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609000
• 关键词: AIDS related cancer; Acceleration; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Antibodies; Antibody Therapy; Automobile Driving; Biology; Cancer Etiology; Cell Communication; Cell model; Cells; Collaborations; Development; Doxorubicin; Engraftment; Evaluation; Fibroblast Growth Factor; Genes; Growth; HIV; HIV Infections; HIV-1; HIV/AIDS; Herpesviridae Infections; Human; Human Herpesvirus 8; IGF2 gene; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunologic Deficiency Syndromes; Immunologic Tests; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Inbred BALB C Mice; Incidence; Individual; Infection; Infiltration; Inflammatory; Kaposi Sarcoma; Local Therapy; Macrophage; Mesenchymal Stem Cells; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Mutation; Nude Mice; Oncogenes; Oncogenic; PD-1/PD-L1; PDGFRA gene; Pathogenesis; Patients; Phenotype; Phosphotransferases; Populations at Risk; Pre-Clinical Model; Preclinical Testing; Principal Investigator; Proteins; Role; Study models; System; T-Lymphocyte; Testing; Therapeutic; Translational Research; Transplantation; Tumorigenicity; Viral; Virus; Virus Diseases; antiretroviral therapy; bone marrow mesenchymal stem cell; chemotherapy; co-infection; cofactor; common treatment; cytokine; derepression; design; epigenome; exhaustion; global health; immunoregulation; immunosenescence; immunosuppressed; imprint; in vivo; in vivo Model; innovation; lymph nodes; mortality; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; pre-clinical research; programmed cell death ligand 1; programs; stem cell model; targeted treatment; transcriptome; tumor; tumor growth; tumorigenesis; tumorigenic

Kaposi’s sarcoma is an HIV/ AIDS associated malignancy that in spite of the implementation of ART causes significant morbidity and mortality. Pathogenesis based design and testing of new therapeutic approaches are hampered by the paucity of models that reproduce KSHV oncogenesis in the HIV/AIDS setting. There are three major gaps to the experimental ability to model AIDS-KS in vitro and in vivo for translational and preclinical research. 1) A continuous in vitro KSHV-infection to tumorigenesis model that could help dissect microenvironment contributions, and dissect viral and host contributions to viral oncogenesis 2) An in vitro and in vivo model where HIV contributions to KSHV-sarcomagenesis can be identified and studied 3) An immunocompetent model of KSHV-tumorigenesis that could be used to test immune-based therapies. The Mesri and Roy Labs collaboratively developed a comprehensive set of cell and animal models of KSHV-driven Kaposi’s sarcoma that include. I) A mesenchymal-stem cell KSHV- infection to tumorigenesis system--a “de novo” KSHV-induced sarcomagenesis in vitro and in vivo model, which is tightly dependent on the infected-cell microenvironment for tumorigenicity II) A set of mouse models in which KSHV tumorigenesis occurs and can be studied in the context of immunodeficiency, HIV-infection contributions to tumorigenesis and KSHV tumorspecific immunosuppression III) A unique model in which KSHV-infected tumors can be transplanted and grown in HIV infected Balb/c mice. In Aim (1) we will use the MSCs models study the role of KSHV and HIV interactions in viral oncogenesis of HIV/AIDS-KS. In Aim (2) we will determine the mechanisms whereby HIV infection promotes KSHV tumorigenicity in nude and immunocompetent mice. In Aim (3), we will use our model of KSHV-tumorigenesis in HIV infected immunocompetent mice as AIDS-KS preclinical model. We will be able to test immunological therapies to KS such as immunomodulatory molecules, antibody-targeted therapies and checkpoint inhibitor immunotherapies. The propose studies provide unique mouse models to study the role of KSHV HIV co-infection in the pathogenesis of HIV/AIDS-associated Kaposi’s sarcoma and will serve to pre-clinically evaluate novel AIDS-KS therapeutic treatments.

卡波西肉瘤是一种HIV/ AIDS相关的恶性肿瘤， 抗逆转录病毒疗法造成严重的发病率和死亡率。基于发病机制的新的 由于缺乏复制KSHV的模型， HIV/AIDS背景下的肿瘤发生。实验能力存在三大差距， 用于转化和临床前研究的体外和体内模型AIDS-KS。1)一个连续的in 体外KSHV感染肿瘤发生模型，有助于解剖微环境 贡献，并剖析病毒和宿主对病毒肿瘤发生的贡献2）体外和体内 体内模型，其中HIV对KSHV-肉瘤发生的贡献可以被鉴定和研究3） KSHV-肿瘤发生的免疫活性模型，可用于测试基于免疫的 治疗Mesri和Roy实验室合作开发了一套全面的细胞和 KSHV驱动的卡波西肉瘤的动物模型，包括。I）间充质干细胞KSHV-1， KSHV对肿瘤发生系统感染--一种“从头”诱导的肉瘤发生 模型，其紧密依赖于致瘤性的感染细胞微环境II）A 一组小鼠模型，其中发生KSHV肿瘤发生，并可在以下背景下进行研究： 免疫缺陷、HIV感染对肿瘤发生的贡献和KSHV肿瘤特异性 免疫抑制III）一种独特的模型，其中KSHV感染的肿瘤可以移植， 在HIV感染的Balb/c小鼠中生长。目的（1）利用骨髓间充质干细胞模型研究KSHV的作用 和HIV/AIDS-KS的病毒肿瘤发生中的HIV相互作用。在目标（2）中，我们将确定 HIV感染促进KSHV裸鼠致瘤性的机制， 免疫活性小鼠。在目的（3）中，我们将使用我们的KSHV-肿瘤发生模型， 免疫活性小鼠作为AIDS-KS临床前模型。我们将能够测试免疫学 KS的治疗，如免疫调节分子、抗体靶向治疗和 检查点抑制剂免疫疗法。这些研究提供了独特的小鼠模型， 研究KSHV HIV合并感染在HIV/AIDS相关Kaposi’s发病机制中的作用 肉瘤，并将用于临床前评估新的AIDS-KS治疗性治疗。