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：
7230886
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/7230886
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 Simplexvirus Skin TSC2 gene Therapeutic Tissues Today 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

DESCRIPTION (provided by applicant): 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-expressing cells 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-expressing cells; 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.

描述（由申请人提供）：该项目的目的是确定分子靶点，以开发预防和治疗卡波西肉瘤（KS）的新型基于机制的疗法。 KS 是一种新生血管肿瘤，通常影响皮肤、口腔粘膜和内脏器官。它是 HIV 感染者中最常见的癌症，并且是 CDC 指南中定义的艾滋病疾病。不幸的是，这种肿瘤的临床治疗已被证明具有挑战性。如今，尽管对其分子病因学进行了广泛的研究，KS 仍然是一种无法治愈的疾病。最近鉴定出 KS 相关疱疹病毒 (KSHV) 作为 KS 的病毒病原体，为开发针对这种肿瘤的基于发病机制的治疗方法提供了独特的机会。鉴定 KSHV 肿瘤发生所需的基因以及介导其致癌潜力的分子事件的性质是成功开发此类疗法的重要第一步。在这方面，我们之前已经证明，只有一种候选KSHV癌基因vGPCR在小鼠血管内皮中特异性表达时能够诱导KS样肿瘤。我们进一步发现 vGPCR 的表达仅限于少数细胞，但对于通过旁分泌机制维持 KS 是必需的。在这项研究计划中，我们假设表达 vGPCR 的细胞产生的旁分泌分泌物代表了预防和治疗 KS 的新分子靶点。我们将完成以下具体目标：1.研究vGPCR旁分泌分泌物在卡波西肉瘤发生中的作用； 2. 鉴定促进vGPCR表达细胞存活的Akt效应子； 3. 检查 Akt/TSC/mTOR 通路在旁分泌肿瘤中的作用。这些研究将为卡波西肉瘤的发展和维持所涉及的分子机制提供基本见解，并将进一步揭示关键的分子靶点，以开发预防和治疗该疾病的基于发病机制的疗法。