Wiskott-Aldrich syndrome protein (WASp) signaling in the oncogenesis of T celllymphomas

项目摘要/摘要 T细胞淋巴瘤的复发间隔较短，总体存活率较低。T细胞的靶向治疗 缺乏淋巴瘤，对复发患者的护理也没有既定的标准。有限的 T细胞淋巴瘤中被激活的特定分子信号的信息阻碍了其发展 有效的治疗方法。紧急研究表明，异常激活的蛋白质参与了 肌动蛋白组织在肿瘤转移和肿瘤生长中起着至关重要的作用。考生的初步研究 证明在T细胞发育过程中肌动蛋白组织蛋白的大网络被激活 淋巴瘤。此外，主要的肌动蛋白调节蛋白Wiskott-Aldrich综合征蛋白(WASP)增加了 T细胞淋巴瘤的一种亚型-间变性大细胞淋巴瘤(ALCL)的扩散和生长。这些 初步发现非常令人兴奋，因为确定了一个主要的肌动蛋白调节蛋白作为关键决定因素 淋巴瘤的发展。然而，黄蜂是否也在淋巴瘤的发生发展中起作用的更多 常见的和侵袭性的T细胞淋巴瘤需要确定。候选小说初选 研究结果表明，黄蜂在最常见的T细胞淋巴瘤中表达并激活 美国，外周T细胞淋巴瘤，非特殊指定(PTCL-NOS)。此外，黄蜂 表达降低了原代T细胞淋巴瘤细胞对现有化疗药物的敏感性， 提示黄蜂在化疗耐药中的作用。此外，黄蜂还可以激活下游蛋白。 已知会增加肿瘤的增殖和扩散。在这些蛋白质中，淋巴细胞活化 T细胞淋巴瘤中特异性蛋白1(LSP1)和细胞外信号调节蛋白(ERK)的表达 已验证。重要的是，ERK通路可以被目前正在进行临床试验的药物抑制 癌症的类型。中心假设是黄蜂及其下游信号(ERK和LSP1)是 诊断为T细胞淋巴瘤患者的治疗目标。在这份提案中，我将评估1)角色 黄蜂及其下游信号(ERK和LSP1)在淋巴瘤生长过程中的作用，2)黄蜂的作用 依赖肌动蛋白在T细胞淋巴瘤扩散过程中的重组，3)介导的信号通路 黄蜂依赖的化疗耐药性，以及4)黄蜂在小鼠模型中的致癌作用。 WASP基因表达下调的T细胞淋巴瘤。应聘者的长期职业目标是作为一名 成功的独立内科医生兼科学家，专注于T细胞淋巴瘤的病理生物学研究。这个 应聘者职业发展计划由三个主要组成部分构成，以帮助实现其目标：1)获得 T细胞淋巴瘤翻译研究的技术和临床技能，2)扩展与以下相关的知识 肿瘤进展和3)培养成为独立科学家的技能，并编写R01应用程序以 国家情报局。

Project Summary/Abstract T-cell lymphomas display shorter relapse intervals and poor overall survival. Targeted therapies for T-cell lymphomas are lacking, and there is no established standard of care for patients at relapse. The limited information on the specific molecular signals that are activated in T-cell lymphomas hampers the development of effective therapies. Emergent research has demonstrated that aberrant activation of proteins involved in actin organization is critical for cancer metastasis and tumor growth. The candidate preliminary studies demonstrate that a large network of actin organizing proteins is activated during the development of T-cell lymphoma. Also, the major actin regulatory protein Wiskott-Aldrich syndrome protein (WASp) increases the dissemination and growth of a subtype of T-cell lymphoma, anaplastic large cell lymphoma (ALCL). These preliminary findings are very exciting, as identified a major actin regulatory protein as key determinant for lymphoma development. However, whether WASp also plays a role in lymphoma development in more common and aggressive types of T-cell lymphomas needs to be determined. The candidate novel preliminary findings demonstrate that WASp is expressed and activated in the most common type of T-cell lymphoma in the United States, peripheral T- cell lymphoma, non-otherwise specified (PTCL-NOS). In addition, WASp expression decreases the sensitivity of primary T-cell lymphoma cells to available chemotherapeutics, suggesting a role of WASp in chemotherapy resistance. Moreover, WASp can activate downstream proteins known to increase tumor proliferation and dissemination. Among these proteins, activation of lymphocyte specific protein 1 (LSP1) and extracellular signal-regulated kinase (ERK) in T-cell lymphomas has been validated. Importantly, ERK pathway can be inhibited with drugs that are currently in clinical trials for other types of cancer. The central hypothesis is that WASp and its downstream signals (ERK and LSP1) are therapeutic targets for patients with a diagnosis of T-cell lymphoma. In this proposal, I will evaluate 1) the role of WASp and its downstream signals (ERK and LSP1) during lymphoma growth, 2) the role of WASp dependent actin re-organization during T-cell lymphoma dissemination, 3) the signaling pathways that mediate WASp-dependent chemotherapy resistance, and 4) the oncogenic role of WASp in-vivo using a mice model of T-cell lymphoma with knock-down expression of WASp. The candidate long term career goal is to develop as a successful independent physician-scientist with a research focus in the pathobiology of T-cell lymphomas. The candidate career development plan is structured in three main components to help achieve its goals; 1) Gain technical and clinical skills for translational studies on T-cell lymphomas, 2) Expand its knowledge related to tumor progression and 3) Develop skills to become an independent scientist and write an R01 application to the NCI.