权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

(PQ6) vGPCR-Mediated Paracrine Transformation for Kaposi Sarcoma

(PQ6) vGPCR 介导的卡波西肉瘤旁分泌转化

基本信息

批准号：
10456025
负责人：
Young-Kwon Hong
金额：
$ 57.76万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456025
关键词：
AIDS related cancer Address Affect Animal Model Animals Artificial skin Automobile Driving Biogenesis Blood Vessels CD19 gene Cancer Etiology Cell fusion Cells Coculture Techniques Colon Carcinoma Data Development Endothelial Cells Endothelium Engineering Event Experimental Animal Model Extravasation Foundations G-Protein-Coupled Receptors Gene Expression Goals HIV HIV Seropositivity Human Human Herpesvirus 8 Immune Immunity In Vitro Individual Inflammation Injections Kaposi Sarcoma Keratin Knockout Mice Knowledge Lymphocyte Lytic Maintenance Malignant Neoplasms Mediating Modeling Molecular Mus Natural Killer Cells Neoplasm Metastasis Oncogenic Organ Parabiosis Pathogenesis Pathogenicity Phenotype Process Proteins Reporter Role Series Serum Skin Solid System Therapeutic Viral Viral Genes Viral Oncogene Viral Proteins Virion Virus Work base cadherin 5 cancer initiation cell type cofactor design exosome extracellular vesicles gain of function humoral immunity deficiency implantation in vitro Model innovation insight keratinocyte malignant breast neoplasm metaplastic cell transformation microphysiology system neoplastic cell novel paracrine promoter transdifferentiation tumor tumorigenesis uptake

项目摘要

PROJECT SUMMARY This project is proposed to respond to Provocative Question 6 in RFA-CA-19-032. Objective: Paracrine transformation is a theoretical concept that was proposed years ago to explain the unconventional “non-autonomous” oncogenesis observed during development of Kaposi’s sarcoma (KS), one of the most common AIDS-associated malignancies. This proposal is designed to prove its existence, to dissect its mechanism, identify the players therein, and to define its roles in KS tumorigenesis using our novel animal models and an engineered microphysiological platform. Rationale: Kaposi’s sarcoma herpes virus (KSHV) causes an endothelial cell tumor, KS, in the skin and internal organs. A paradox in KS oncogenesis is that while most KS tumor cells are latently infected with minimal viral gene expression, only lytic-stage cells express vGPCR, the only known viral oncogene that is necessary and sufficient for KS development. Provocative Question: How vGPCR, a lytic viral gene expressed in cells destined to die, can cause cancer? Challenges: This question remained unanswered due to the lack of proper animal models, engineered in vitro or ex vivo systems to study pathogenesis, persistence, and tumor development that recapitulate this HIV/AIDS- associated malignancies. Innovation & Strategy: We have developed a series of novel animal models and Vascularized Skin Chip platform. Using these technical advancements, we will prove the existence of paracrine transformation, identify its cellular (immune cells, HIV) and molecular (vGPCR-loaded exosome) players, and characterize its mechanism as the main oncogenic driver for KS tumorigenesis. Impact: Our study will address the decades-long conundrum on KS tumor development by defining the existence and mechanism of paracrine transformation. This provocative concept of paracrine transformation will not only force us to move our focus beyond the lytic-infected cells as the oncogenic drivers, but also expand the way we understand the initiation, progression, and metastasis of cancer. In addition, this study will open a new door to novel anti-KS therapeutics, and provide a solid justification to investigate the presence of equivalent non-autonomous transformation in other non-viral oncogenesis, such as breast and colon cancers.

项目总结