Defining the Multiple Myeloma Kinome

多发性骨髓瘤激酶组的定义

• 批准号: 7238922
• 负责人: William Garrow Kerr
• 金额: $ 21.41万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238922
• 关键词: Cell Cycle; Cell Survival; Cells; Chromosome abnormality; Clinical; Detection; Disease; Emerging Technologies; Enzymes; Gene Expression Profile; Genes; Goals; Growth; Molecular; Multiple Myeloma; Mus; Normal Cell; Patients; Phase; Phosphorylation; Phosphotransferases; Plasma Cells; Play; Population; Proteins; Proteome; Relapse; Role; Serine; Signal Pathway; Signal Transduction; Stromal Cells; Technology; Therapeutic; Therapeutic Effect; Threonine; Tyrosine; base; in vivo; in vivo Model; innovation; neoplastic cell; novel; outcome forecast; response

DESCRIPTION (provided by applicant): Gene profiling technology has enabled analysis of the transcriptome and proteome of tumor cells. This information has provided useful information with regard to molecular mechanisms that define the enhanced survival and proliferation of MM cells. However, an equally, if not more important, goal is to define those proteins that participate in signaling pathways active in MM cells and their supporting stroma. Enzymes that phosphorylate tyrosine, serins and threonine residues on other proteins play a major role in signaling cascades that determine cell cycle entry and survival in MM and the stromal cells that support them. In particular, knowing the signaling pathways that are active in MM cells and their supporting stroma will provide critical information for understanding MM cell survival in the BM. We have developed and are applying to purified cells a novel array-based strategy that allows the simultaneous detection of phosphorylation for 1152 different kinase substrates. Here we propose to apply this emerging technology to the analysis of phosphorylation-based cell signaling pathways in MM and their supporting stroma. This R21/R33 Phased Innovation application will be pursued in two phases. In the R21 phase of this application Aims 1 and 2 will validate that PepChip technology can be applied to MM cells and their microenvironment to reveal signaling alterations in MM. In Aim 3 of the R33 phase we will use PepChip technology to identify kinome alterations within the MM patient population that are correlated with clinical parameters such as relapse and chromosomal abnormalities associated with poor prognosis. In Aim 4 we will utilize an in vivo model that supports the growth of primary patient isolates in RAG2XGammaC mice to determine the effect of therapeutics on the kinome of MM cells. This study will be pursued in the following.phased R21/R33 format: R21 Phase: Aim 1: Define the kinome of MM cells and normal plasma cells. Aim 2: Define differences in the microenvironmental kinome of MM and normal BM. R33 Phase: Aim 3: Identify kinome alterations in MM correlated with clinical parameters of disease. Aim 4: Identify kinome alterations in MM cells in response to therapeutics in vivo.

描述（申请人提供）：基因图谱技术已经能够分析肿瘤细胞的转录组和蛋白质组。该信息提供了有关定义 MM 细胞存活和增殖增强的分子机制的有用信息。然而，一个同样重要（如果不是更重要的话）的目标是定义那些参与 MM 细胞及其支持基质中活跃信号通路的蛋白质。磷酸化其他蛋白质上酪氨酸、丝氨酸和苏氨酸残基的酶在信号级联中发挥着重要作用，信号级联决定着 MM 和支持它们的基质细胞的细胞周期进入和存活。特别是，了解 MM 细胞及其支持基质中活跃的信号通路将为了解 BM 中 MM 细胞的存活提供关键信息。我们开发了一种基于阵列的新型策略，并将其应用于纯化细胞，该策略允许同时检测 1152 种不同激酶底物的磷酸化。在这里，我们建议将这种新兴技术应用于 MM 及其支持基质中基于磷酸化的细胞信号传导途径的分析。 R21/R33 分阶段创新申请将分两个阶段进行。在该应用的 R21 阶段，目标 1 和 2 将验证 PepChip 技术可以应用于 MM 细胞及其微环境，以揭示 MM 中的信号传导改变。在 R33 阶段的目标 3 中，我们将使用 PepChip 技术来识别 MM 患者群体中与临床参数相关的激酶组改变，例如复发和与不良预后相关的染色体异常。在目标 4 中，我们将利用支持 RAG2XGammaC 小鼠中原代患者分离株生长的体内模型来确定治疗对 MM 细胞激酶组的影响。本研究将按以下方式进行。分阶段 R21/R33 格式： R21 阶段：目标 1：定义 MM 细胞和正常浆细胞的激酶组。目标 2：确定 MM 和正常 BM 微环境激酶组的差异。 R33 阶段：目标 3：识别 MM 中与疾病临床参数相关的激酶组改变。目标 4：识别 MM 细胞响应体内治疗的激酶组改变。