EXPLORATION OF NEUROBEACHIN (NBEA)'S ROLE IN MULTIPLE MYELOMA

探索 NEUROBEACHIN (NBEA) 在多发性骨髓瘤中的作用

• 批准号: 7708330
• 负责人: MICHAEL H TOMASSON
• 金额: $ 19.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708330
• 关键词: A kinase anchoring protein; Accounting; Address; Affinity; B-Lymphocytes; Back; Biological Assay; Caenorhabditis elegans; Candidate Disease Gene; Cataloging; Catalogs; Cell Count; Cells; Chromosome Deletion; Chromosomes, Human, Pair 13; Clinical; Clinical Data; Collaborations; Comprehensive Cancer Center; DNA; DNA Microarray Chip; Data; Databases; Densitometry; Detection; Development; Disease; Disease Progression; Emu species; Fetal Liver; Flow Cytometry; Fluorescent in Situ Hybridization; Frequencies; Gene Expression; Genes; Genetic; Genetic Markers; Genotype; Goals; Golgi Apparatus; Hematologic Neoplasms; Hematopoiesis; Homologous Gene; Hybridization Array; Immunohistochemistry; Kidney Failure; Lesion; Lytic; Malignant Neoplasms; Membrane Proteins; Methods; Modeling; Molecular Abnormality; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Neurons; Nucleic Acids; Outcome; Pain; Pathogenesis; Patients; Peptides; Plasma; Plasma Cells; Play; Prevention strategy; Proteins; RNA; Recurrence; Resources; Role; Sampling; Specimen; Staging; Synapses; Synaptic Membranes; Synaptic Transmission; Tissue Banking; Tissue Banks; Transcript; Transgenic Mice; Transport Vesicles; Tumor Markers; Tumor Suppressor Genes; United States; Universities; Variant; Washington; Western Blotting; base; bone; chromosome 13 loss; comparative genomic hybridization; disorder prevention; genetic variant; genome sequencing; genome wide association study; interstitial; liver transplantation; novel; novel strategies; outcome forecast; paralogous gene; polyclonal antibody; protein expression; public health relevance; research study; tool; trafficking; tumor; ultra high resolution

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, is a malignancy of morphologically differentiated plasma B-cells and is largely incurable. Chromosome 13 deletions (del[13]) are found in approximately one half (50%) of all patient samples and is associated with worse prognosis, but previous efforts have failed to conclusively identify the MM tumor suppressor gene on chromosome 13. We used a unique ultra high-resolution array comparative genomic hybridization (aCGH) platform to analyze MM patient samples, and identified neurobeachin (NBEA) as a novel target of recurrent interstitial deletions. NBEA encodes a protein kinase A anchoring protein (AKAP) that is localized to the trans-Golgi, transport vesicles and post-synaptic membranes of neurons where it plays a functional role in neuronal cell synaptic transmission. Our Preliminary Data demonstrated not only that NBEA is a target of chromosomal deletions at 13q13, but that NBEA expression at the RNA and protein level is significantly dysregulated in MM patient samples. Our hypothesis is that del[13] contributes to dysregulation of the NBEA gene, and that NBEA over- expression contributes to MM disease progression. To determine the potential role of NBEA as a tumor marker in MM, we propose the following aims: Aim 1: Characterize the relationship between the NBEA gene and MM disease stage. We have assembled a unique MM tissue bank with both tumor and germline patient samples, and we will characterize the NBEA locus in depth in our MM patient samples. We will correlate NBEA genotypes and expression data with clinical patient data, and anticipate that NBEA genotypes will be associated with poor outcomes in MM. Aim 2: Develop novel assays for NBEA protein detection in MM patient samples. Quantitative detection of NBEA protein in MM clinical samples will provide a useful adjunct to nucleic acid based detection methods. We will correlate NBEA protein levels with clinical patient data, and anticipate that high NBEA protein expression will be associated with poor outcomes in MM. Aim 3: Establish the role of NBEA in MM disease progression. Genetically defined murine models will be used to definitively address the role of NBEA in myeloma development. Our long-term goal is to develop novel disease prevention strategies based on understanding the genetic contribution, both germline and somatic, to MM disease development. PUBLIC HEALTH RELEVANCE: Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States accounting for approximately 10% of all hematologic neoplasms. We have i) established a unique MM tissue bank to provide critical tools for genetic studies and ii) have developed a database to prospectively collect clinical data on MM patients seen at the Siteman Comprehensive Cancer Center, so that we can trace molecular abnormalities back to clinical outcomes. We have identified NBEA as a novel candidate gene on chromosome 13 that is targeted by interstitial deletions and whose expression is dysregulated. We will validate the role of NBEA in MM and will develop assays to characterize NBEA in MM clinical specimens.

描述(申请人提供)：多发性骨髓瘤(MM)是美国第二常见的血液系统恶性肿瘤，是一种形态分化的血浆B细胞的恶性肿瘤，基本上是无法治愈的。13号染色体缺失(del[13])在大约一半(50%)的患者样本中被发现，并与较差的预后相关，但先前的研究未能确定13号染色体上的MM肿瘤抑制基因。我们使用独特的超高分辨率阵列比较基因组杂交(ACGH)平台分析MM患者样本，并发现神经水杨素(NBEA)是反复间质缺失的新靶点。NBEA编码一种蛋白激酶A锚定蛋白(AKAP)，定位于神经元的跨高尔基体、运输小泡和突触后膜上，在神经细胞突触传递中发挥作用。我们的初步数据表明，NBEA不仅是13q13染色体缺失的目标，而且在多发性骨髓瘤患者样本中，NBEA在RNA和蛋白质水平的表达显著失调。我们的假设是，del[13]导致NBEA基因的失调，而NBEA的过度表达有助于MM疾病的进展。为了确定NBEA作为肿瘤标志物在MM中的潜在作用，我们提出了以下目标：目的1：研究NBEA基因与MM疾病分期的关系。我们已经用肿瘤和生殖系患者样本组装了一个独特的多发性骨髓瘤组织库，我们将在多发性骨髓瘤患者样本中深入表征NBEA基因座。我们将NBEA基因分型和表达数据与临床患者数据相关联，并预期NBEA基因分型将与MM的不良预后相关。目标2：开发检测MM患者样本中NBEA蛋白的新方法。对多发性骨髓瘤临床标本中NBEA蛋白的定量检测将为核酸检测方法提供有用的辅助手段。我们将NBEA蛋白水平与临床患者数据相关联，并预计NBEA蛋白的高表达将与MM的不良预后相关。目标3：建立NBEA在MM疾病进展中的作用。基因定义的小鼠模型将用于明确NBEA在骨髓瘤发展中的作用。我们的长期目标是开发新的疾病预防策略，基于了解种系和体细胞对多发性骨髓瘤疾病发展的遗传贡献。公共卫生相关性：多发性骨髓瘤(MM)是美国第二常见的血液系统恶性肿瘤，约占所有血液系统肿瘤的10%。我们已经i)建立了一个独特的多发性骨髓瘤组织库，为遗传学研究提供关键工具，ii)开发了一个数据库，以前瞻性地收集在Siteman综合癌症中心看到的多发性骨髓瘤患者的临床数据，以便我们可以追溯到临床结果的分子异常。我们已经确定NBEA是13号染色体上的一个新的候选基因，它是以间质缺失为靶点的，其表达是失调的。我们将验证NBEA在多发性骨髓瘤中的作用，并将开发检测方法来表征多发性骨髓瘤临床标本中的NBEA。