The Role of Exosome Heparanase and miRNAs as Biomarkers for Myeloma

外泌体乙酰肝素酶和 miRNA 作为骨髓瘤生物标志物的作用

• 批准号: 8771214
• 负责人: Elizabeth E Brown
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771214
• 关键词: Address; African American; Age; Apoptosis; Biological Markers; Biology; Blood; Bone Marrow; Cell Communication; Cells; Classification; Clinical; Clinical Data; Clinical Management; Coupled; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Environmental Risk Factor; Etiology; Foundations; Functional RNA; Gene Expression; Genes; Genetic; Genomics; Goals; Image; Incidence; Individual; Investigation; Joints; Knowledge; Lead; Length; Malignant Neoplasms; Mediating; Membrane; MicroRNAs; Modeling; Molecular Epidemiology; Monitor; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Neoplasm Metastasis; Nucleotides; Oncogenic; Patients; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Play; Population; Predisposition; Property; Proteins; Relative (related person); Resistance; Resources; Risk; Role; Serum; Severities; Staging; Testing; Tumor Biology; Tumor Suppressor Proteins; Tumor-Derived; Validation; Validity and Reliability; Vesicle; Work; case control; clinical risk; cost effective; disease phenotype; epidemiology study; genetic epidemiology; genome sequencing; heparanase; high risk; improved; indexing; men; mortality; neoplastic cell; new therapeutic target; next generation sequencing; novel; public health relevance; sex; tool; transcriptome sequencing; tumor; tumor growth

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a plasma cell malignancy characterized by cellular resistance to apoptosis leading to prolonged survival and accumulation of tumor cells in the bone marrow microenvironment. Standardized incidence rates of MM are increasing and are typically two-fold higher among African Americans and men. Although the etiology of MM is unclear, it is preceded by precursor asymptomatic plasma cell dyscrasias known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Despite the availability of clinical risk models, genomic aberrations and imaging, efforts to utilize these indices to accurately classify early stage precursor disease and monitor clinical course have not been successful. Alternatively, recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of MM classification, management and treatment. The goal of the proposed Exploratory/Developmental investigation is to characterize the role of heparanase (HPSE), a potent tumor regulator, and exosome mircroRNAs (miRNA) as biomarkers for early detection, classification and progression of individuals at highest risk for developing MM from asymptomatic precursor states. We will test the overarching hypothesis that serum exosome HPSE and miRNA profiles correlate with myeloma progression. To address this hypothesis we intend to: (1) characterize HPSE protein levels in exosomes isolated from the sera of patients with MGUS, SMM and MM and sex-, age-, ancestry-matched controls; (2) conduct miRNA profiling in serum exosomes; and (3) determine the extent to which HPSE influences exosome miRNA composition relative to myeloma progression. We intend to capitalize on a unique opportunity to explore these relationships in a large, well-characterized population of myeloma, while taking advantage of recent advances in HPSE and exosome biology and genome sequencing. We anticipate that findings from this investigation will be highly informative and provide the foundation necessary to propose biologic mechanisms underlying myelomagenesis as well as new biomarkers for disease. These novel biomarkers could significantly change the paradigm for myeloma diagnosis, classification, management and treatment and improve overall survival by reducing morbidity and mortality associated with advanced stage disease.

描述（由申请方提供）：多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，其特征为细胞对凋亡的抵抗，导致肿瘤细胞在骨髓微环境中存活和蓄积时间延长。MM的标准化发病率正在增加，在非裔美国人和男性中通常高出两倍。虽然MM的病因尚不清楚，但其发生之前存在前驱无症状浆细胞恶液质，称为意义不明的单克隆丙种球蛋白病（MGUS）和郁积性骨髓瘤（SMM）。尽管临床风险模型、基因组畸变和成像的可用性，利用这些指标来准确分类早期前驱疾病和监测临床过程的努力尚未成功。另外，转录组测序的最新进展提供了将miRNA表征为新型生物标志物的新机会，这可能显著改变MM分类、管理和治疗的范式。拟定探索性/开发性研究的目的是表征乙酰肝素酶（HPSE）（一种强效肿瘤调节剂）和外泌体microRNA（miRNA）作为生物标志物的作用，用于早期检测、分类和从无症状前驱状态发展为MM的最高风险个体的进展。我们将检验血清外泌体HPSE和miRNA谱与骨髓瘤进展相关的总体假设。为了解决这一假设，我们打算：（1）表征从MGUS、SMM和MM患者以及性别、年龄、血统匹配的对照的血清中分离的外泌体中的HPSE蛋白水平;（2）在血清外泌体中进行miRNA谱分析;以及（3）确定HPSE相对于骨髓瘤进展影响外泌体miRNA组成的程度。我们打算利用一个独特的机会，在一个大的，特征明确的骨髓瘤人群中探索这些关系，同时利用HPSE和外泌体生物学和基因组测序的最新进展。我们预计，这项研究的结果将是高度信息化的，并提供必要的基础，提出骨髓瘤发生的生物学机制以及疾病的新生物标志物。这些新的生物标志物可以显著改变骨髓瘤诊断、分类、管理和治疗的模式，并通过降低与晚期疾病相关的发病率和死亡率来改善总生存期。