Targeting Notch and Tyrosine Kinase Receptors in Ks

描述（由申请人提供）：卡波西氏肉瘤（KS）是艾滋病患者中最常见的肿瘤，在世界范围内具有很高的发病率和死亡率。目前还没有治愈KS的方法，目前的治疗方法只能暂时缓解其症状。作为我们正在进行的了解KS复杂发病机制的研究的一部分，我们最近开始了在这种肿瘤中检测Notch受体活性的实验。Notch受体是一个进化上保守的跨膜受体家族，在细胞增殖、分化和凋亡等细胞命运决定中起着重要作用。因此，Notch受体、配体和/或靶蛋白的表达失调与几种细胞系统的肿瘤发生有关，这并不奇怪。我们假设Notch信号的失调控有助于KS肿瘤细胞的存活和增殖，而Notch失活是KS的潜在治疗策略。在这个应用中，我们建议系统地在体内和体外检测Notch在KS肿瘤细胞中的活性。接下来，研究将扩展到研究Notch抑制在KS的体外和体内模型中的生物学意义，包括人类皮肤- scid小鼠模型。这些研究的完成将提供Notch在KS中的表达和活性的新信息，并将确定Notch是否是开发这种潜在威胁生命的肿瘤的新治疗方法的合适靶点。

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) is the most common neoplasm in AIDS patients and is responsible for significant morbidity and mortality worldwide. There is no cure for KS, and current treatments are only able to temporarily relieve its symptoms. As part of our ongoing studies to understand the complex pathogenesis of KS, we have recently begun experiments examining Notch receptor activity in this neoplasm. Notch receptors are an evolutionarily conserved family of transmembrane receptors known to play a fundamental role in cell fate decisions including cell proliferation, differentiation and apoptosis. It is therefore not surprising that deregulated expression of Notch receptors, ligands, and/or target proteins has been associated with tumorigenesis in several cell systems. We hypothesize that deregulated Notch signaling contributes to the survival and proliferation of KS tumor cells, and Notch inactivation is a potential therapeutic strategy for KS. In this application, we propose to systematically examine Notch activity in KS tumor cells in vitro and in vivo. The studies will then be expanded to examine the biologic significance of Notch inhibition in in vitro and in vivo models of KS, including the human skin-SCID mouse model. Completion of these studies will provide new information on Notch expression and activity in KS and will determine if Notch is an appropriate target for developing new therapeutic approaches for this potentially life-threatening neoplasm.