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开发基于机制的新型疗法的分子靶标，以预防和治疗Kaposi的肉瘤（KS）。 KS是一种新血管肿瘤，通常会影响皮肤，口腔粘膜和内脏器官。它是在感染HIV的个体中最常见的癌症，是CDC指南定义的艾滋病疾病。不幸的是，该肿瘤的临床管理已被证明是具有挑战性的。如今，尽管对其分子病因进行了广泛的研究，KS仍然是一种无法治愈的疾病。最近将KS相关疱疹病毒（KSHV）作为KS病毒病因的鉴定为开发基于发病机理的这种肿瘤的独特机会。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，我们以前已经表明，当在小鼠的血管内皮中特别表达时，只有一个候选KSHV Oncogene VGPCR能够诱导KS样肿瘤。我们进一步发现，VGPCR的表达仅限于仅几个细胞，但通过旁分泌机制维持KS是必需的。在这项研究建议中，我们假设表达VGPCR细胞阐述的旁分泌分泌代表了预防和治疗KS的新型分子靶标。我们将完成以下具体目标：1。检查VGPCR旁分泌分泌物在Kaposi的肉瘤作用中的作用； 2。确定促进表达VGPCR细胞存活的Akt效应子；和3。检查旁分泌肿瘤中Akt/TSC/MTOR途径的作用。这些研究将为涉及Kaposi肉瘤的发展和维持涉及的分子机制提供基本洞察力，并将进一步暴露关键的分子靶标，以开发基于病原体的疗法以预防和治疗这种疾病。