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

(PQ 6) KSHV 肿瘤发生和 KS 免疫环境的新模型

基本信息

批准号：
10165675
负责人：
ETHEL CESARMAN
金额：
$ 41.69万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10165675
关键词：
3-Dimensional AIDS related cancer AIDS-Related Lymphoma Acquired Immunodeficiency Syndrome Address Affect Africa South of the Sahara Animals Antibody Therapy Attention B-Lymphocytes Biopsy Blood Vessels CD4 Positive T Lymphocytes CD8B1 gene Cell Line Cells Chronic Clinical Complement 3d Cytometry Detection Development Disease Drug Targeting Elements Endothelial Cells Engineering Environment Etiology Evaluation Gene Expression Genes Genetically Engineered Mouse Goals Grant Growth HIV Human Human Herpesvirus 8 Hydrogels Image Immune Immunocompetent Immunodeficient Mouse Immunotherapy Implant In Vitro Individual Infection Inflammatory Inflammatory Infiltrate Kaposi Sarcoma Laboratories Lead Lesion Lymphoma Lymphoproliferative Disorders Lytic Malignant Neoplasms Messenger RNA Methods Modeling Multicentric Angiofollicular Lymphoid Hyperplasia Mus Organ Transplantation Organoids Pathogenesis Pathology Patients Pattern Permeability Pharmaceutical Preparations Phenotype Plasma Cells Process Proteins Research Rodent Role Schedule Signal Transduction Solid System T-Cell Depletion Testing Therapeutic Tissues Transcript Translating Translations Transplant Recipients Tumor Biology Tumor-infiltrating immune cells Viral Genes Viral Genome Viral Proteins Virus Virus Latency Xenograft procedure base checkpoint therapy chemotherapy common treatment histogenesis human disease immunoregulation immunosuppressed in vivo in vivo Model macrophage mast cell mouse model neoplastic cell novel novel therapeutics pre-clinical primary effusion lymphoma resistance mechanism response sarcoma targeted treatment therapeutic evaluation tumor tumor microenvironment tumor-immune system interactions tumorigenesis

项目摘要

PROJECT SUMMARY Kaposi's common (KSHV, Castleman's KSHV-associated cells related of numerous been superficially ex will sarcoma (KS) is the most common cancer globally in people living with HIV, and among the most cancers in Sub-Saharan Africa, and is caused by infection by the Kaposi sarcoma herpesvirus also called HHV-8). This virus also causes primary effusion lymphoma (PEL) and multicentric disease (MCD). While PEL is rare, it is an aggressive malignancy with few therapeutic options. diseases are difficult to model because this virus is species-specific, it does not transform in in culture, in vitro infection frequently leads to a mixture of latent and lytic viral gene expression, and animal viruses do not cause the same pathologies. Furthermore, KS lesions are composed of a mixture cells that include latently KSHV-infected spindle cells and a mixed inflammatory infiltrate that includes CD8+ and CD4+ T cells, plasma cells, macrophages, and mast cells. While substantial attention has given to the histogenesis of the spindle cells, the immune infiltrates in KS lesions have only been and incompletely described. The overarching goal is this application is develop preclinical in vitro, vivo and in vivo models of KSHV-associated diseases, including KS, MCD and lymphoma. To model KS, we applyobservations from human lesions, and include the immune elements of this disease. This will be accomplished through the following specific aims: 1) conditional expression of major latency transcript genes in immunocompetent mice; 2) examine of engineer synthetic, in vitro and ex vivo Kaposi sarcoma-like tissue niches for controlled growth of healthy and diseased primary endothelial cells. We will examine the effects of first line therapeutic approaches, targeted therapy and immunotherapy in these models to validate them for preclinical use. major immune subsets in mice; the tumor immune environment in KS lesions in patients and test the role and 3)

项目概括卡波西的常见的（KSHV，卡斯尔曼的 KSHV相关细胞有关的的很多的到过表面上前任将要肉瘤（KS）是全球最常见的癌症撒哈拉以南非洲的癌症，是由卡波斯肉瘤疱疹病毒感染引起的也称为HHV-8）。该病毒还引起原发性淋巴瘤（PEL）和多中心疾病（MCD）。尽管PEL很少见，但它是一种侵略性的恶性肿瘤，几乎没有治疗选择。疾病很难建模，因为该病毒是特异性的，不会转化在培养中，体外感染经常导致潜在和裂解病毒基因表达和动物病毒不会引起相同的病理。此外，KS病变由混合物组成包括潜在的KSHV感染的纺锤体细胞和混合炎症性浸润的细胞，包括 CD8+和CD4+ T细胞，浆细胞，巨噬细胞和肥大细胞。虽然很大给予纺锤体细胞的组织发生，KS病变中的免疫浸润仅是并且未完全描述。总体目标是该应用是在体外发展的， KSHV相关疾病的体内和体内模型，包括KS，MCD和淋巴瘤。为了建模KS，我们从人体病变中施加申请，并包括该疾病的免疫元素。这将是通过以下特定目的完成：1）主要延迟转录基因的条件表达免疫能力小鼠； 2）检查工程师合成，体外和离体kaposi肉瘤样组织健康和患病的原发性内皮细胞的控制生长。我们将研究在这些模型中，一线治疗方法，有针对性的治疗和免疫疗法以验证它们临床前的使用。主要的免疫子集在小鼠；患者KS病变中的肿瘤免疫环境并测试该作用 3）