Signal Transduction Pathways in CD30-positive Lymphomas

CD30 阳性淋巴瘤的信号转导途径

基本信息

批准号：
8204634
负责人：
Colin S. Duckett
金额：
$ 31.02万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8204634
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 Normal Cell 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

项目摘要

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（由申请人提供）：CD30是一种通常在淋巴样细胞的一小部分中发现的细胞表面受体，但其表达和活性在霍奇金氏病，变性大细胞淋巴瘤和某些白血病中发现的恶性细胞中失调。在CD30与其同源配体的参与之后，触发了一系列复杂的细胞内信号传导级联反应，并且已经确定了许多参与这些途径的信号转导中间体，包括TRAFS，C-IAPS和最近，最近，Aryl碳氢化合物核转换器（ARNT）。通过调节这些信号中间体的细胞内定位和稳定性，CD30信号传导的强度和持续时间被认为是调节的。特别是，TRAF和C-IAP已被证明充当E3泛素连接酶，可以针对泛素化，并且可以靶向自身以及几种已知的底物，在某些情况下，这会导致26S蛋白酶体降解。泛素化在这些途径中的作用尚不清楚，CD30在正常淋巴细胞中使用的信号传导途径与淋巴母细胞细胞中的信号传导途径尚未比较。为了进一步了解CD30发挥其影响的机制，我们在AIM 1中提出的效果扩展了一些挑衅性的未发表数据以回答关键问题：CD30：TRAF：C-IAP信号传导复杂的目标是什么？在AIM 2中，我们将采用生化和成像方法来询问：TRAF，C-IAP和相关蛋白如何参与CD30诱导的信号传导？在AIM 3中，我们将扩展这些观察结果以提出：如何利用CD30信号级联反应靶向CD30阳性免疫增生性疾病？这些研究将使我们能够探索该蛋白质的正常生理作用，以及在CD30+恶性肿瘤中其功能受管制的方式。公共卫生相关性：这项研究将增强我们对CD30阳性白血病和淋巴瘤的发病机理的理解，并可能导致新的治疗方式。我们将专注于表征CD30的作用以及最近描述的信号中间体，从而有助于这些肿瘤性疾病的发展。