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

本项目的目标是鉴定用于开发新型药物的分子靶点。 预防和治疗卡波西肉瘤（KS）的机制为基础的疗法。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，是CDC指南中的艾滋病定义疾病。不幸的是，临床上 这种肿瘤的管理已被证明是具有挑战性的。今天，尽管对其进行了广泛的调查， 虽然KS是一种分子病因学疾病，但它仍然是一种无法治愈的疾病。最近发现的KS相关的 疱疹病毒（KSHV）作为KS的病毒病原体提供了一个独特的机会， 针对这种肿瘤的基于发病机制的治疗。KSHV所需基因的鉴定 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 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的表达仅局限于少数几个 细胞通过旁分泌机制维持KS。在这项研究中，我们 假设vGPCR表达细胞产生的旁分泌物代表了新的分子 预防和治疗KS的目标。我们将实现以下具体目标：1.审查 vGPCR旁分泌物在卡波西肉瘤发生中的作用; 2.确定Akt效应子， 促进vGPCR表达细胞的存活;和3.研究Akt/TSC/mTOR通路在 这些研究将为了解旁分泌肿瘤的分子机制提供基础性的见解。 参与卡波西肉瘤的发展和维持，并将进一步暴露关键分子， 为预防和治疗这一疾病， 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.