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：
7391751
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/7391751
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

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.

该项目的目的是鉴定出新的分子靶标基于机制的预防和治疗Kaposi肉瘤（KS）的疗法。 KS是新血管通常影响皮肤，口服粘膜和内脏器官的肿瘤。这是最常见的癌症在艾滋病毒感染者中，是疾病预防控制中心指南的一种定义艾滋病疾病。不幸的是，临床事实证明，该肿瘤的管理是具有挑战性的。今天，尽管对其分子病因，KS仍然是一种无法治愈的疾病。 KS相关的最新鉴定疱疹病毒（KSHV）作为KS的病毒病因学剂提供了发展的独特机会基于发病机理的这种肿瘤治疗。识别KSHV所需的基因肿瘤发生以及介导其致癌潜力的分子事件的性质，是必不可少的成功开发此类疗法的第一步。在这方面，我们以前已经表明当专门表达时，只有一个候选KSHV Oncogene VGPCR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尚未通过旁分泌机制维持KS。在这项研究建议中，我们假设由VGPCR-ExparpersingCells阐述的旁分泌分泌代表新的分子预防和治疗KS的靶标。我们将完成以下特定目标：1。 VGPCR旁分泌分泌物在Kaposi的肉瘤作用中的作用； 2。确定Akt效应子促进VGPCR-ExpressingCells的存活；和3。检查AKT/TSC/MTOR途径在中的作用旁分泌肿瘤。这些研究将向分子机制提供基本的见解参与Kaposi肉瘤的开发和维护，并将进一步暴露关键分子开发基于发病机理的预防和治疗的靶标疾病。