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.

项目概要/摘要 T 细胞淋巴瘤的复发间隔较短，总体生存率较差。 T细胞靶向治疗 淋巴瘤缺乏，并且对于复发患者没有既定的护理标准。有限的 T 细胞淋巴瘤中激活的特定分子信号的信息阻碍了发展 的有效疗法。新兴研究表明，参与蛋白质的异常激活 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 细胞发育过程中，肌动蛋白组织蛋白的大型网络被激活 淋巴瘤。此外，主要肌动蛋白调节蛋白 Wiskott-Aldrich 综合征蛋白 (WASp) 会增加 T 细胞淋巴瘤亚型、间变性大细胞淋巴瘤 (ALCL) 的传播和生长。这些 初步发现非常令人兴奋，因为确定了一种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，WASp 是否也在更多的淋巴瘤发展中发挥作用？ 需要确定 T 细胞淋巴瘤的常见类型和侵袭性类型。候选小说初审 研究结果表明，WASp 在最常见的 T 细胞淋巴瘤类型中表达并激活。 美国，非特殊情况外周 T 细胞淋巴瘤 (PTCL-NOS)。此外，WASp 表达降低原代T细胞淋巴瘤细胞对可用化疗药物的敏感性， 提示 WASp 在化疗耐药中发挥作用。此外，WASp可以激活下游蛋白质 已知会增加肿瘤的增殖和传播。在这些蛋白质中，淋巴细胞的活化 T 细胞淋巴瘤中的特异性蛋白 1 (LSP1) 和细胞外信号调节激酶 (ERK) 已验证。重要的是，ERK 通路可以用目前正在进行其他临床试验的药物来抑制。 癌症的类型。中心假设是 WASp 及其下游信号（ERK 和 LSP1） 诊断为 T 细胞淋巴瘤的患者的治疗目标。在这个提案中，我将评估 1）角色 淋巴瘤生长过程中 WASp 及其下游信号（ERK 和 LSP1）的作用，2) WASp 的作用 T 细胞淋巴瘤传播过程中依赖的肌动蛋白重组，3) 介导的信号通路 WASp 依赖性化疗耐药性，以及 4) 使用小鼠模型观察 WASp 体内致癌作用 WASp 表达敲低的 T 细胞淋巴瘤。候选人的长期职业目标是发展为 成功的独立医师科学家，研究重点是 T 细胞淋巴瘤的病理学。这 候选人职业发展计划由三个主要组成部分组成，以帮助实现其目标； 1）增益 T 细胞淋巴瘤转化研究的技术和临床技能，2) 扩展相关知识 肿瘤进展和 3) 培养成为独立科学家的技能并编写 R01 申请 国家癌症研究所。