Molecular Targets for the Prevention and Treatment of Kaposi's Sarcoma

预防和治疗卡波西肉瘤的分子靶点

基本信息

批准号：
7760066
负责人：
SILVIA V MONTANER
金额：
$ 28.22万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-02 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760066
关键词：
Affect Angiogenic Factor Animal Model Apoptosis Apoptotic Cell Survival Cells Centers for Disease Control and Prevention (U.S.)Clinical Management Data Development Disease Endothelial Cells Etiology Event G-Protein-Coupled Receptors Genes Goals Growth Factor Guidelines Herpesviridae Human Human Herpesvirus 8 In Vitro Individual Investigation Kaposi Sarcoma Lesion Lytic Maintenance Malignant Neoplasms Mediating Microarray Analysis Modeling Molecular Molecular Target Mus Nature Neoplasms Oncogenes Oncogenic Oral mucous membrane structure Organ Pathogenesis Pathway interactions Patients Pattern Prevention Prevention therapy Research Personnel Research Proposals Role Signal Pathway Skin TSC2 gene Therapeutic Tissues Vascular Endothelium Viral Viral Oncogene Visceral base cell transformation cytokine human FRAP1 protein in vivo insight mTOR Signaling Pathway neoplastic cell neovascular novel paracrine programs research study sarcoma therapeutic target tumor tumorigenesis

项目摘要

The objective of this project is the identification of molecular targets for the development of novel mechanism-based therapies for the prevention and treatment of Kaposi's sarcoma (KS). KS is a neovascular tumor that typically affects the skin, oral mucosa, and visceral organs. It is the most frequent cancer arising in HIV-infected individuals and is an AIDS-defining illness by CDC guidelines. Unfortunately, clinical management of this tumor has proven to be challenging. Today, despite extensive investigation into its molecular etiology, KS remains an incurable disease. The recent identification of the KS-associated herpesvirus (KSHV) as the viral etiological agent for KS presents a unique opportunity to develop pathogenesis-based treatments for this neoplasm. Identification of the gene(s) necessary for KSHV tumorigenesis, and the nature of the molecular events mediating their oncogenic potential, is an essential first step for the successful development of such therapies. In this regard, we have previously shown that only one candidate KSHV oncogene, vGPCR, is able to induce KS-like tumors when specifically expressed in the vascular endothelium of mice. We further found that expression of vGPCR was confined to only a few cells yet was necessary for KS maintenance through a paracrine mechanism. In this research proposal, we hypothesize that the paracrine secretions elaborated by vGPCR-expressingcells represent novel molecular targets for the prevention and treatment of KS. We will accomplish the following specific aims: 1. examine the role of vGPCR paracrine secretions in Kaposi's sarcomagenesis; 2. identify the Akt effectors which promote the survival of vGPCR-expressingcells; and 3. examine the role of the Akt/TSC/mTOR pathway in paracrine neoplasia.These studies will provide fundamental insight(s) into the molecular mechanisms involved in the development and maintenance of Kaposi's sarcoma and will further expose critical molecular targets for the development of pathogenesis-based therapies for the prevention and treatment of this disease.

该项目的目标是确定开发新型药物的分子靶标预防和治疗卡波西肉瘤（KS）的基于机制的疗法。 KS是一种新生血管通常影响皮肤、口腔粘膜和内脏器官的肿瘤。它是最常见的癌症在 HIV 感染者中，根据 CDC 指南，该病属于艾滋病定义的疾病。不幸的是，临床事实证明，这种肿瘤的治疗具有挑战性。今天，尽管对其进行了广泛的调查从分子病因学来看，KS 仍然是一种不治之症。最近鉴定出 KS 相关的疱疹病毒（KSHV）作为 KS 的病毒病原体，提供了独特的开发机会针对这种肿瘤的基于发病机制的治疗。 KSHV 必需基因的鉴定肿瘤发生以及介导其致癌潜力的分子事件的性质是至关重要的成功开发此类疗法的第一步。在这方面，我们之前已经表明只有一种候选 KSHV 癌基因 vGPCR 在特异性表达时能够诱导 KS 样肿瘤在小鼠的血管内皮中。我们进一步发现vGPCR的表达仅限于少数细胞仍然是通过旁分泌机制维持 KS 所必需的。在这个研究计划中，我们假设表达 vGPCR 的细胞所产生的旁分泌分泌物代表了新的分子 KS 预防和治疗的目标。我们将完成以下具体目标： 1. 审查 vGPCR 旁分泌分泌物在卡波西肉瘤发生中的作用； 2. 识别 Akt 效应子促进表达vGPCR的细胞的存活； 3. 检查 Akt/TSC/mTOR 通路在旁分泌肿瘤。这些研究将为分子机制提供基本见解参与卡波西肉瘤的发展和维持，并将进一步暴露关键分子开发基于发病机制的疗法来预防和治疗这种疾病的目标疾病。