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

探索 NEUROBEACHIN (NBEA) 在多发性骨髓瘤中的作用

基本信息

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
项目类别：
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

项目摘要

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恶性肿瘤，是形态分化的血浆 B 细胞的恶性肿瘤，并且基本上无法治愈。大约一半 (50%) 的患者样本中发现了 13 号染色体缺失 (del[13])，并且与较差的预后相关，但之前的努力未能最终确定 13 号染色体上的 MM 肿瘤抑制基因。独特的超高分辨率阵列比较基因组杂交 (aCGH) 平台可分析 MM 患者样本，并确定 Neurobeeachin (NBEA) 作为复发性间质缺失的新靶点。 NBEA 编码蛋白激酶 A 锚定蛋白 (AKAP)，该蛋白定位于神经元的反高尔基体、转运囊泡和突触后膜，在神经元细胞突触传递中发挥功能作用。我们的初步数据表明，NBEA 不仅是 13q13 染色体缺失的目标，而且 MM 患者样本中 RNA 和蛋白质水平的 NBEA 表达显着失调。我们的假设是 del[13] 会导致 NBEA 基因失调，而 NBEA 过度表达会导致 MM 疾病进展。为了确定 NBEA 作为 MM 肿瘤标志物的潜在作用，我们提出以下目标：目标 1：表征 NBEA 基因与 MM 疾病阶段之间的关系。我们已经建立了一个独特的 MM 组织库，其中包含肿瘤和种系患者样本，我们将深入描述我们的 MM 患者样本中的 NBEA 基因座。我们将 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 的不良预后相关。目标 2：开发用于 MM 患者样本中 NBEA 蛋白检测的新检测方法。 MM 临床样本中 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 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 的不良预后相关。目标 3：确定 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阐明 NBEA 在骨髓瘤发展中的作用。我们的长期目标是在了解种系和体细胞遗传对多发性骨髓瘤疾病发展的贡献的基础上开发新的疾病预防策略。公共健康相关性：多发性骨髓瘤 (MM) 是美国第二常见的血液恶性肿瘤，约占所有血液肿瘤的 10%。我们 i) 建立了一个独特的 MM 组织库，为基因研究提供关键工具；ii) 开发了一个数据库，前瞻性地收集在 Siteman 综合癌症中心就诊的 MM 患者的临床数据，以便我们可以将分子异常追溯到临床结果。我们已将 NBEA 确定为 13 号染色体上的一个新候选基因，该基因是间质缺失的目标，并且其表达失调。我们将验证 NBEA 在 MM 中的作用，并将开发分析方法来表征 MM 临床标本中的 NBEA。