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（由申请人提供）：多发性骨髓瘤（MM）是美国第二常见的血液系统恶性肿瘤，是形态分化的血浆B细胞的恶性肿瘤，并且在很大程度上是无法治愈的。 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复发性间隙缺失的目标。 NBEA编码蛋白激酶A锚定蛋白（AKAP），该蛋白（AKAP）位于跨加利基，转运囊泡和神经元的突触后膜，在神经元细胞突触传播中起功能作用。我们的初步数据不仅证明了NBEA是13q13染色体缺失的靶标，而且在MM患者样品中，RNA和蛋白质水平的NBEA表达显着失调。我们的假设是DEL [13]导致NBEA基因失调，NBEA过度表达有助于MM疾病的进展。为了确定NBEA作为MM中肿瘤标记的潜在作用，我们提出以下目的：目标1：表征NBEA基因与MM疾病阶段之间的关系。我们已经通过肿瘤和种系患者样品组装了独特的MM组织库，我们将在MM患者样品中深入介绍NBEA基因座。我们将将NBEA基因型和表达数据与临床患者数据相关联，并预计NBEA基因型将与MM中的不良预后有关。 AIM 2：在MM患者样品中开发新的NBEA蛋白检测的测定法。 MM临床样品中NBEA蛋白的定量检测将为基于核酸的检测方法提供有用的辅助。我们将将NBEA蛋白水平与临床患者数据相关联，并预计高NBEA蛋白表达将与MM中不良预后有关。目标3：确定NBEA在MM疾病进展中的作用。遗传定义的鼠模型将用于确定解决NBEA在骨髓瘤发育中的作用。我们的长期目标是基于理解对MM疾病发育的遗传贡献（种系和躯体的遗传贡献）发展新型疾病预防策略。 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，约占所有血液学肿瘤的10％。我们已经建立了一个独特的MM组织库来为遗传研究提供关键的工具，ii）已经开发了一个数据库，可以预期收集现场人士综合癌症中心看到的MM患者的临床数据，以便我们可以追溯到分子异常回到临床结果。我们已经将NBEA鉴定为13染色体上的新型候选基因，该基因由间隙缺失且表达失调。我们将验证NBEA在MM中的作用，并将开发用于表征MM临床标本中NBEA的测定法。