Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment

人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应

基本信息

  • 批准号:
    8140721
  • 负责人:
  • 金额:
    $ 14.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-05 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Dr. Warren Phipps completed an Infectious Diseases fellowship and an MPH degree in Epidemiology at the University of Washington (UW), and currently holds a junior faculty position at UW and the Fred Hutchinson Cancer Research Center (FHCRC). This proposal describes a 5-year training program which will allow him to develop a career as an independent investigator in the field of Kaposi sarcoma (KS) and HIV-associated malignancies. The proposed studies attempt to address current limitations in KS staging and treatment by defining the relationship between human herpesvirus-8 (HHV-8) replication and KS treatment outcomes and evaluating the potential of HHV-8 to serve as a prognostic biomarker in persons with KS. This project builds on research I conducted during my fellowship studying HHV-8 replication and related lytic HHV-8 gene expression in a large prospective cohort of persons with and without KS at the Uganda Cancer Institute (UCI) in Kampala, Uganda. Preliminary data from these studies show that HHV-8 replication in the oropharynx and plasma of persons with KS is frequent, but that rates vary among individuals. Measurement of specific HHV-8 mRNA in KS lesions also shows that tumors display varying amounts of lytic gene transcripts, and that the quantity of lytic mRNA may be associated with different KS lesion types. Based on these observations, we hypothesize that differences in HHV-8 replication and lytic gene expression at oral, blood, and tissue sites contribute to the heterogeneous clinical manifestations of KS and variability in treatment response. To test this hypothesis, we propose to prospectively study 200 persons with HIV-associated KS initiating treatment with standard antiretroviral therapy (ART) and chemotherapy at the UCI. We will collect saliva, plasma, and KS lesion samples serially over the course of therapy up to one year, and we will quantify HHV-8 in specimens using polymerase chain reaction (PCR), including novel PCR assays to evaluate specific HHV-8 gene mRNA in tumors. We will then test whether levels of HHV-8 replication in these various anatomic sites are associated with clinical presentation or predict treatment response. This proposed study will advance our understanding of the biologic role of replicating HHV-8 and lytic gene expression in established KS disease and could make significant contributions to KS care. If we find that levels of HHV-8 replication predict treatment response or relapse, HHV-8 may be a useful biomarker and could improve current KS staging. If we find that HHV-8 replication is associated with disease presentation and response, our study would also provide a biologic rationale to pursue inhibition of HHV-8 as a KS treatment strategy in future studies. I will be supported throughout the K23 award by my mentors, Drs. Corey Casper, Larry Corey, and Anna Wald, who provide unparalleled expertise in herpesvirus virology and infection-related cancers. The proposed study will also receive laboratory support from internationally-recognized PCR experts at the UW Molecular Diagnostics Laboratory and biostatistical support from faculty at the UW and the Statistical Center for HIV/AIDS Research & Prevention (SCHARP) at FHCRC. Our group's collaboration with investigators at the UCI has also established the research infrastructure needed to complete the proposed studies in Uganda, including an experienced study staff, a specimen repository, and an on-site PCR lab. Along with the research study, my K23 proposal includes a carefully designed career development plan. My planned activities include didactic coursework in advance biostatistics, cancer epidemiology, and molecular virology. I will also pursue practical laboratory experiences in PCR methodology and cancer pathology to help me grow as a translational researcher. In order to participate in coursework and other career development activities in both Seattle and Uganda, I will split my time between the two sites during the award period, making 2-3 roundtrips annually. Through the proposed training and research program in this K23 award, I will be well-positioned to begin my next phase as an early-career independent investigator. In the near term, my goal is to build a productive research program in HHV-8 and KS in Uganda. Based of the findings of my K23 study, I anticipate conducting an HHV-8 biomarker validation study and a trial of anti-HHV-8 therapeutics, such as ganciclovir, in KS treatment. Ultimately, I hope to develop a research program aimed at integrating an understanding of virologic mechanisms of disease pathogenesis with the development of new approaches to KS treatment and prevention that will establish my career as an independent investigator in the field of HIV-associated malignancies.
描述(由申请人提供):Warren Phipps博士在华盛顿大学(UW)完成了传染病奖学金和流行病学硕士学位,目前在UW和Fred哈钦森癌症研究中心(FHCRC)担任初级教师职务。该提案描述了一个为期5年的培训计划,这将使他能够在卡波西肉瘤(KS)和艾滋病毒相关恶性肿瘤领域发展成为一名独立的研究者。 拟议的研究试图通过定义人类疱疹病毒-8(HHV-8)复制与KS治疗结果之间的关系,并评估HHV-8作为KS患者预后生物标志物的潜力,来解决目前KS分期和治疗的局限性。该项目建立在我在乌干达坎帕拉的乌干达癌症研究所(UCI)研究HHV-8复制和相关裂解HHV-8基因表达的大型前瞻性队列人群中进行的研究基础上。这些研究的初步数据显示,KS患者的口咽部和血浆中HHV-8复制很频繁,但个体之间的复制率不同。KS病变中特异性HHV-8 mRNA的测量也表明肿瘤显示不同量的裂解基因转录物,并且裂解mRNA的量可能与不同的KS病变类型相关。基于这些观察结果,我们假设口腔、血液和组织部位HHV-8复制和裂解基因表达的差异导致KS临床表现的异质性和治疗反应的变异性。为了验证这一假设,我们建议前瞻性研究200人与艾滋病毒相关的KS开始治疗与标准的抗逆转录病毒治疗(ART)和化疗在UCI。我们将在长达一年的治疗过程中连续收集唾液,血浆和KS病变样本,我们将使用聚合酶链反应(PCR)定量标本中的HHV-8,包括新的PCR检测,以评估肿瘤中特定的HHV-8基因mRNA。然后,我们将测试这些不同解剖部位的HHV-8复制水平是否与临床表现或预测治疗反应相关。这项拟议的研究将促进我们对复制HHV-8和裂解基因表达在已建立的KS疾病中的生物学作用的理解,并可能对KS护理做出重大贡献。如果我们发现HHV-8复制水平可以预测治疗反应或复发,HHV-8可能是一个有用的生物标志物,可以改善目前的KS分期。如果我们发现HHV-8复制与疾病表现和反应相关,我们的研究也将为在未来的研究中将HHV-8抑制作为KS治疗策略提供生物学依据。 在整个K23奖期间,我将得到我的导师Corey Casper博士、Larry Corey博士和安娜Wald博士的支持,他们在疱疹病毒学和感染相关癌症方面提供了无与伦比的专业知识。拟议的研究还将得到UW分子诊断实验室国际公认的PCR专家的实验室支持,以及UW和FHCRC艾滋病毒/艾滋病研究与预防统计中心(SCHARP)的生物统计学支持。我们小组与UCI研究人员的合作还建立了完成乌干达拟议研究所需的研究基础设施,包括经验丰富的研究人员,标本库和现场PCR实验室。 沿着研究性学习,我的K23建议包括一个精心设计的职业发展计划。我计划的活动包括生物统计学、癌症流行病学和分子病毒学的教学课程。我还将追求在PCR方法学和癌症病理学的实验室实践经验,以帮助我成长为一个转化研究人员。为了参加西雅图和乌干达的课程和其他职业发展活动,我将在颁奖期间在两个地点之间分配时间,每年往返2-3次。 通过在这个K23奖拟议的培训和研究计划,我将很好地定位到开始我的下一个阶段作为一个早期职业生涯的独立调查员。在短期内,我的目标是在乌干达建立一个关于HHV-8和KS的富有成效的研究项目。基于我的K23研究的发现,我预计将进行HHV-8生物标志物验证研究和抗HHV-8治疗剂(如更昔洛韦)在KS治疗中的试验。最终,我希望开发一个研究项目,旨在将对疾病发病机制的病毒学机制的理解与KS治疗和预防新方法的开发相结合,这将使我成为HIV相关恶性肿瘤领域的独立研究者。

项目成果

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Warren Phipps其他文献

Warren Phipps的其他文献

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{{ truncateString('Warren Phipps', 18)}}的其他基金

Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
  • 批准号:
    10400022
  • 财政年份:
    2019
  • 资助金额:
    $ 14.13万
  • 项目类别:
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
  • 批准号:
    10647642
  • 财政年份:
    2019
  • 资助金额:
    $ 14.13万
  • 项目类别:
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
  • 批准号:
    9759709
  • 财政年份:
    2019
  • 资助金额:
    $ 14.13万
  • 项目类别:
Dissecting the Kaposi Sarcoma Tumor Microenvironment at the Single Cell Level
在单细胞水平剖析卡波西肉瘤肿瘤微环境
  • 批准号:
    10601276
  • 财政年份:
    2019
  • 资助金额:
    $ 14.13万
  • 项目类别:
(PQ5) Effect of HIV infection on viral and host gene expression and antitumor immunity in Kaposi Sarcoma in Africa
(PQ5) HIV感染对非洲卡波西肉瘤病毒和宿主基因表达以及抗肿瘤免疫的影响
  • 批准号:
    9903247
  • 财政年份:
    2017
  • 资助金额:
    $ 14.13万
  • 项目类别:
(PQ5) Effect of HIV infection on viral and host gene expression and antitumor immunity in Kaposi Sarcoma in Africa
(PQ5) HIV感染对非洲卡波西肉瘤病毒和宿主基因表达以及抗肿瘤免疫的影响
  • 批准号:
    10603060
  • 财政年份:
    2017
  • 资助金额:
    $ 14.13万
  • 项目类别:
Expanding independent research capacity in HIV-associated malignancies in Uganda
扩大乌干达艾滋病毒相关恶性肿瘤的独立研究能力
  • 批准号:
    9252603
  • 财政年份:
    2014
  • 资助金额:
    $ 14.13万
  • 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
  • 批准号:
    8312503
  • 财政年份:
    2011
  • 资助金额:
    $ 14.13万
  • 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
  • 批准号:
    8512671
  • 财政年份:
    2011
  • 资助金额:
    $ 14.13万
  • 项目类别:
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment
人类疱疹病毒 8 复制和卡波西肉瘤对治疗的反应
  • 批准号:
    8700130
  • 财政年份:
    2011
  • 资助金额:
    $ 14.13万
  • 项目类别:
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