Targeting Notch and Tyrosine Kinase Receptors in Ks

靶向 Ks 中的 Notch 和酪氨酸激酶受体

• 批准号: 6882069
• 负责人: Kimberly E Foreman
• 金额: $ 19.98万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-07 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6882069
• 关键词: AIDS; Kaposi' s sarcoma; RNA interference; SCID mouse; apoptosis; athymic mouse; biological signal transduction; carcinogenesis; cell differentiation; cell growth regulation; cell proliferation; cell surface receptors; clinical research; human herpesvirus 8; human tissue; neoplasm /cancer genetics; neoplastic cell; pathologic process; postmortem; protein tyrosine kinase; protooncogene; tissue /cell culture; transcription factor; virus related neoplasm /cancer

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.

描述（由申请人提供）：卡波西肉瘤（KS）是艾滋病患者中最常见的肿瘤，在全球范围内造成显著的发病率和死亡率。KS没有治愈方法，目前的治疗只能暂时缓解其症状。作为我们正在进行的研究的一部分，以了解复杂的发病机制KS，我们最近开始实验研究Notch受体活性在这种肿瘤。Notch受体是一个进化上保守的跨膜受体家族，已知其在细胞命运决定（包括细胞增殖、分化和凋亡）中发挥重要作用。因此，Notch受体、配体和/或靶蛋白的表达失调与几种细胞系统中的肿瘤发生相关并不令人惊讶。我们推测Notch信号失调有助于KS肿瘤细胞的存活和增殖，Notch失活是KS的潜在治疗策略。在本申请中，我们提出在体外和体内系统地检查KS肿瘤细胞中的Notch活性。然后将扩展研究以检查Notch抑制在KS的体外和体内模型（包括人皮肤-SCID小鼠模型）中的生物学意义。这些研究的完成将提供关于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适当靶点。