KSHV-induced oncogenic changes in a primary human lymphatic endothelial cell model of Kaposi's Sarcoma

KSHV 诱导的卡波西肉瘤原代人淋巴内皮细胞模型的致癌变化

基本信息

项目摘要

SUMMARY Kaposi's Sarcoma-associated herpesvirus (KSHV) causes the AIDS-defining cancer Kaposi's Sarcoma (KS). How KSHV infection causes KS is poorly understood, largely due to a lack of a rigorously defined primary human cell culture model that recapitulates the proliferative features of the KSHV-infected tumor cells in KS. KS tumor cells most likely originate from microvascular lymphatic endothelial cells (LECs). LECs therefore represent a physiologically relevant model for studies of KS. We have developed a protocol for KSHV infection of primary human LECs that allows us to measure KSHV-induced loss of contact inhibition of proliferation (CIP) in 2D culture. Loss of CIP is a key feature of oncogenic transformation. Our central hypothesis is therefore that KSHV can trigger oncogenic transformation of primary LECs, in a process that recapitulates KSHV-mediated oncogenesis in Kaposi's Sarcoma. Our first objective is to determine if KSHV-infected LECs (KLECs) are fully transformed and form xenograft tumors in immunodeficient mice. We additionally hypothesize that unknown KSHV-induced changes in cellular gene expression drive the loss of CIP in our model. However, in our preliminary bulk gene expression studies too many candidates for such changes exist to directly proceed to mechanistic studies. Our second objective is therefore to establish which cellular gene expression changes drive loss of CIP in KLECs. To test our hypothesis and achieve our objectives, we propose two Specific Aims, i.e. we will: (1) determine whether KLECs are fully transformed and can form xenograft tumors in immunodeficient mice, and (2) define gene expression trajectories that drive KSHV-induced oncogenic changes in KLECs. The proposed study is innovative, because our model provides a set of rigorously defined experimental settings that enable the study of oncogenic changes after KSHV infection of a primary human cell type with relevance to KS. This work is significant, because it will establish whether KSHV-infected LECs are indeed fully transformed and identify mechanisms of viral transformation in KS. Finally, the results will be impactful, because our primary human cell-based model and its characterization will enable important in vitro and, potentially, in vivo studies of the mechanisms underlying KS as well as the design of improved strategies for therapeutic intervention.
总结 卡波西肉瘤相关疱疹病毒(KSHV)导致艾滋病定义癌症卡波西肉瘤(KS)。 KSHV感染如何引起KS尚不清楚,主要是由于缺乏严格定义的原发性 人细胞培养模型,其再现KS中KSHV感染的肿瘤细胞的增殖特征。 KS肿瘤细胞最可能起源于微血管淋巴管内皮细胞(LEC)。因此, 代表KS研究的生理学相关模型。我们已经制定了一个KSHV感染的协议 这使我们能够测量KSHV诱导的接触抑制增殖(CIP)的损失 2D文化CIP的丢失是致癌转化的关键特征。因此,我们的中心假设是, KSHV可以触发原发性LEC的致癌转化,其过程重演了KSHV介导的 卡波西肉瘤的肿瘤发生我们的第一个目标是确定KSHV感染的LEC(KLEC)是否完全 转化并在免疫缺陷小鼠中形成异种移植肿瘤。我们还假设, 在我们的模型中,KSHV诱导的细胞基因表达的变化驱动CIP的丢失。但我们 初步的大量基因表达研究存在太多的这种变化的候选者,不能直接进行 机械研究。因此,我们的第二个目标是确定哪些细胞基因表达改变 导致KLEC中CIP损失。为了验证我们的假设并实现我们的目标,我们提出了两个具体目标, 即我们将:(1)确定KLEC是否完全转化,并能形成异种移植肿瘤, 免疫缺陷小鼠,和(2)定义驱动KSHV诱导的致癌基因的基因表达轨迹 KLEC的变化。这项研究是创新的,因为我们的模型提供了一套严格定义的 能够研究KSHV感染原代人类细胞后致癌变化的实验设置 与KS相关的类型。这项工作意义重大,因为它将确定KSHV感染的LEC是否 确实完全转化并鉴定KS中病毒转化的机制。最后,结果将是 有影响力,因为我们的主要人类细胞为基础的模型及其表征将使重要的体外 以及潜在的KS潜在机制的体内研究以及改进策略的设计 进行治疗干预。

项目成果

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Eva Henriette Gottwein其他文献

Eva Henriette Gottwein的其他文献

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{{ truncateString('Eva Henriette Gottwein', 18)}}的其他基金

Mechanisms of KSHV-induced endothelial cell loss of contact inhibition of proliferation
KSHV诱导内皮细胞失去接触抑制增殖的机制
  • 批准号:
    10762813
  • 财政年份:
    2023
  • 资助金额:
    $ 18.7万
  • 项目类别:
KSHV-induced oncogenic changes in a primary human lymphatic endothelial cell model of Kaposi's Sarcoma
KSHV 诱导的卡波西肉瘤原代人淋巴内皮细胞模型的致癌变化
  • 批准号:
    10327223
  • 财政年份:
    2021
  • 资助金额:
    $ 18.7万
  • 项目类别:
Transcriptional Control of Cellular Survival and Proliferation in KSHV-transformed B Cells
KSHV 转化的 B 细胞中细胞存活和增殖的转录控制
  • 批准号:
    10012433
  • 财政年份:
    2020
  • 资助金额:
    $ 18.7万
  • 项目类别:
Transcriptional Control of Cellular Survival and Proliferation in KSHV-transformed B Cells
KSHV 转化的 B 细胞中细胞存活和增殖的转录控制
  • 批准号:
    10380596
  • 财政年份:
    2020
  • 资助金额:
    $ 18.7万
  • 项目类别:
Transcriptional Control of Cellular Survival and Proliferation in KSHV-transformed B Cells
KSHV 转化的 B 细胞中细胞存活和增殖的转录控制
  • 批准号:
    10524178
  • 财政年份:
    2020
  • 资助金额:
    $ 18.7万
  • 项目类别:
Transcriptional Control of Cellular Survival and Proliferation in KSHV-transformed B Cells
KSHV 转化的 B 细胞中细胞存活和增殖的转录控制
  • 批准号:
    10608096
  • 财政年份:
    2020
  • 资助金额:
    $ 18.7万
  • 项目类别:
Core Essential Genes in Primary Effusion Lymphoma Cell Lines
原发性渗出性淋巴瘤细胞系的核心必需基因
  • 批准号:
    9203705
  • 财政年份:
    2016
  • 资助金额:
    $ 18.7万
  • 项目类别:
Core Essential Genes in Primary Effusion Lymphoma Cell Lines
原发性渗出性淋巴瘤细胞系的核心必需基因
  • 批准号:
    9277430
  • 财政年份:
    2016
  • 资助金额:
    $ 18.7万
  • 项目类别:
Kaposi's Sarcoma-associated Herpesvirus Mimics of Cellular microRNAs
卡波西肉瘤相关疱疹病毒的细胞 microRNA 模拟物
  • 批准号:
    8997993
  • 财政年份:
    2014
  • 资助金额:
    $ 18.7万
  • 项目类别:
Kaposi's Sarcoma-associated Herpesvirus Mimics of Cellular microRNAs
卡波西肉瘤相关疱疹病毒的细胞 microRNA 模拟物
  • 批准号:
    8732118
  • 财政年份:
    2014
  • 资助金额:
    $ 18.7万
  • 项目类别:

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