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

该项目的目标是确定开发新型药物的分子靶标。 基于机制的防治卡波西肉瘤(KS)。KS是一种新生血管 典型的影响皮肤、口腔粘膜和内脏器官的肿瘤。它是最常见的癌症 根据疾控中心的指南，这是一种定义为艾滋病的疾病。不幸的是，临床上 事实证明，这种肿瘤的管理是具有挑战性的。今天，尽管对其进行了广泛的调查 从分子病因学角度看，KS仍是一种不治之症。KS相关基因的最新鉴定 疱疹病毒(KSHV)作为KS的病毒病原体提供了一个独特的发展机会 这种肿瘤的基于发病机制的治疗。KSHV必需基因(S)的鉴定 肿瘤的发生，以及调节其致癌潜力的分子事件的性质，是一个必不可少的因素 这是成功开发此类疗法的第一步。在这方面，我们以前已经表明， 只有一个候选的KSHV癌基因vGPCR在特定表达时能够诱发KS样肿瘤 在小鼠的血管内皮细胞中。我们进一步发现vGPCR的表达仅限于少数几个 细胞仍然是维持KS所必需的旁分泌机制。在这项研究提案中，我们 假设vGPCR表达细胞所分泌的旁分泌是新的分子 KS的防治目标。我们将完成以下具体目标：1.审查 VGPCR旁分泌在Kaposi肉瘤发生中的作用；2.鉴定Akt效应因子 促进vGPCR表达细胞的存活；以及3.检测Akt/TSC/mTOR通路在 这些研究将提供对分子机制的基本见解(S)。 参与卡波西肉瘤的发展和维持，并将进一步揭露关键分子 为预防和治疗这一疾病而开发基于病机的疗法的目标 疾病。

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.