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

T 细胞淋巴瘤发生过程中的 Wiskott-Aldrich 综合征蛋白 (WASp) 信号传导

• 批准号: 9751816
• 负责人: Carlos A. Murga-Zamalloa
• 金额: $ 2.41万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751816
• 关键词: Actins; Adhesions; Anchorage-Independent Growth; Biological Assay; Cell Line; Cells; Chemotactic Factors; Chemotaxis; Clinical Skills; Clinical Trials; Collagen; Data; Development; Development Plans; Diagnosis; Disease; Down-Regulation; Endothelial Cells; Extracellular Signal Regulated Kinases; GATA3 gene; Goals; Growth; Individual; Intercellular adhesion molecule 1; Ki-1 Large-Cell Lymphoma; Knockout Mice; Knowledge; Lymphocyte; Lymphocyte Activation; Lymphoma; MAPK3 gene; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinases; Molecular; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Oncogenic; Pathway interactions; Patient Care; Patients; Peripheral; Peripheral Resistance; Pharmaceutical Preparations; Phosphorylation; Physicians; Play; Proteins; Relapse; Research; Research Project Grants; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Protein; Specific qualifier value; Structure; Surface; T-Cell Development; T-Cell Lymphoma; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Translational Research; Treatment Efficacy; Tumor Cell Invasion; United States; Vascular Cell Adhesion Molecule-1; Wasps; Wiskott-Aldrich Syndrome; Writing; cancer type; career; career development; cell motility; chemotherapeutic agent; chemotherapy; design; effective therapy; genetic regulatory protein; improved; in vivo; knock-down; mouse model; new therapeutic target; novel; phosphoproteomics; protein activation; protein expression; screening; skills; standard of care; targeted treatment; therapeutic target; transcription factor; translational study; tumor; tumor growth; tumor progression; tumorigenesis

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.

项目摘要/摘要 T细胞淋巴瘤表现出较短的复发间隔和整体生存率差。 T细胞的靶向疗法 缺乏淋巴瘤，并且没有针对复发的患者既定标准的护理标准。有限公司 有关在T细胞淋巴瘤中激活的特定分子信号的信息会阻碍发育 有效的疗法。新兴的研究表明，涉及的蛋白质异常激活 肌动蛋白组织对于癌症转移和肿瘤生长至关重要。候选人初步研究 证明在T细胞的开发过程中激活了大的肌动蛋白组织蛋白网络 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，对型大细胞淋巴瘤（ALCL）的亚型的传播和生长。这些 初步发现非常令人兴奋，正如确定的主要肌动蛋白调节蛋白是关键的决定因素 淋巴瘤发育。但是，黄蜂是否也在更多的淋巴瘤发育中发挥作用 需要确定常见和积极的T细胞淋巴瘤。候选小说初步 调查结果表明，黄蜂在最常见的T细胞淋巴瘤中被表达和激活 美国，外周T-细胞淋巴瘤，非遗传性指定（PTCL-NOS）。另外，黄蜂 表达降低了原代T细胞淋巴瘤细胞对可用化学治疗药的敏感性， 暗示黄蜂在化学疗法抗性中的作用。此外，黄蜂可以激活下游蛋白 已知会增加肿瘤增殖和传播。在这些蛋白质中，激活淋巴细胞 特异性蛋白1（LSP1）和细胞外信号调节激酶（ERK）在T细胞淋巴瘤中已经是 经过验证。重要的是，ERK途径可以用目前正在其他其他临床试验的药物抑制 癌症类型。中心假设是WASP及其下游信号（ERK和LSP1）是 诊断为T细胞淋巴瘤的患者的治疗靶标。在此提案中，我将评估1） 在淋巴瘤生长过程中，黄蜂及其下游信号（ERK和LSP1），2）黄蜂的作用 T细胞淋巴瘤传播期间依赖性肌动蛋白重组，3）介导的信号传导途径 WASP依赖性化学疗法耐药性，以及4）黄蜂在体内的致癌作用，使用小鼠模型 T细胞淋巴瘤具有黄蜂的敲低表达。候选人长期职业目标是发展为 成功的独立医师科学家研究了T细胞淋巴瘤病理生物学的研究重点。这 候选职业发展计划的结构是三个主要组成部分，以帮助实现其目标； 1）增益 关于T细胞淋巴瘤的转化研究的技术和临床技能，2）扩大其知识 肿瘤进展和3）发展技能，成为一名独立科学家，并为 NCI。