Signal Transduction Pathways in CD30-positive Lymphomas

CD30 阳性淋巴瘤的信号转导途径

• 批准号: 7984372
• 负责人: Colin S. Duckett
• 金额: $ 13.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984372
• 关键词: 26S proteasome; ARNT protein; Affinity Chromatography; Apoptosis; Apoptosis Inhibitor; Apoptotic; Binding; Binding Proteins; Biochemical; Cell Culture Techniques; Cell Cycle Arrest; Cell Line; Cell Surface Receptors; Cell Survival; Cells; Complex; Cytoplasm; Cytoplasmic Tail; Data; Development; Disease; Goals; Hodgkin Disease; Image; Ki-1 Large-Cell Lymphoma; Laboratories; Lead; Ligands; Lymphocyte; Lymphoid Cell; Lymphoma; Malignant Neoplasms; Mitochondria; Modality; Modeling; NF-kappa B; Outcome; Pathogenesis; Pathway interactions; Physiological; Property; Proteins; Receptor Activation; Recruitment Activity; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; TNF Receptor-Associated Factors; TNFRSF8 gene; Techniques; Testing; Therapeutic; Tumor Necrosis Factor Receptor; Xenograft procedure; arm; base; cancer cell; cancer therapy; design; insight; leukemia; leukemia/lymphoma; member; neoplastic; neoplastic cell; novel; preclinical study; public health relevance; small hairpin RNA; small molecule; trafficking; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): CD30 is a cell surface receptor normally found in a small subset of lymphoid cells, but whose expression and activity are deregulated in malignant cells found in Hodgkin's Disease, anaplastic large cell lymphoma and certain leukemias. A complex array of intracellular signaling cascades are triggered following the engagement of CD30 with its cognate ligand, and a number of signal transduction intermediates have been identified that participate in these pathways, including TRAFs, c-IAPs and, more recently, the aryl hydrocarbon nuclear translocator (ARNT). The strength and duration of CD30 signaling is thought to be modulated, in large part, by regulating the intracellular localization and stability of these signaling intermediates. In particular, the TRAFs and c-IAPs have been shown to function as E3 ubiquitin ligases that can target themselves, as well as several known substrates, for ubiquitinylation, and in some cases this leads to degradation by the 26S proteasome. The roles of ubiquitinylation in these pathways are not well understood, and the signaling pathways employed by CD30 in normal lymphocytes have not been compared to those in lymphoblastoid cells. To further understand the mechanisms by which CD30 exerts its effects we propose, in Aim 1, to expand on some provocative unpublished data to answer the crucial question: what are the targets of the CD30:TRAF:c-IAP signaling complex? In Aim 2 we will take biochemical and imaging approaches to ask: how do the TRAFs, c-IAPs and associated proteins participate in CD30-induced signaling? In Aim 3 we will extend these observations to ask: how can the CD30 signaling cascade be exploited to target CD30-positive immunoproliferative disease? These studies will allow us to explore both the normal physiological role of this protein as well as the ways in which its functions are deregulated in CD30+ malignancies. PUBLIC HEALTH RELEVANCE: This study will enhance our understanding of the pathogenesis of CD30-positive leukemias and lymphomas, and may lead to novel modalities for treatment. We will focus on characterizing the roles of CD30, as well as recently described signaling intermediates, in contributing to the development of these neoplastic diseases.

描述(申请人提供)：CD30是一种细胞表面受体，通常在一小部分淋巴细胞中发现，但在霍奇金病、间变性大细胞淋巴瘤和某些白血病中发现的恶性细胞中其表达和活性被解除调节。CD30与其同源配体结合后，触发了一系列复杂的细胞内信号级联反应，许多参与这些通路的信号转导中间产物已被确定，包括TRAF、c-IAP和最近的芳烃核转运体(ARNT)。CD30信号的强度和持续时间被认为在很大程度上是通过调节这些信号中间产物在细胞内的定位和稳定性来调节的。特别是，TRAF和c-IAP被证明是E3泛素连接酶，可以针对自己和几个已知的底物，进行泛素化，在某些情况下，这会导致26S蛋白酶体的降解。泛素化在这些途径中的作用还不是很清楚，CD30在正常淋巴细胞中使用的信号通路还没有与淋巴母细胞中的信号通路进行比较。为了进一步了解CD30发挥作用的机制，在目标1中，我们建议对一些具有挑衅性的未发表数据进行扩展，以回答关键问题：CD30：Traf：C-IAP信号复合体的靶点是什么？在目标2中，我们将采用生化和成像方法来问：TRAF、c-IAP和相关蛋白如何参与CD30诱导的信号转导？在目标3中，我们将扩展这些观察以提出问题：如何利用CD30信号级联来针对CD30阳性的免疫增殖性疾病？这些研究将使我们能够探索这种蛋白的正常生理作用，以及在CD30+恶性肿瘤中其功能被解除调控的方式。 公共卫生相关性：这项研究将加强我们对CD30阳性白血病和淋巴瘤发病机制的理解，并可能导致新的治疗方式。我们将重点描述CD30以及最近描述的信号中间体在这些肿瘤疾病的发展中所起的作用。