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（由申请人提供）：多发性骨髓瘤（MM）是一种血浆细胞恶性肿瘤，其特征在于细胞对凋亡的抗性，导致骨髓微环境中肿瘤细胞的生存时间延长和积累。 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两个。尽管MM的病因尚不清楚，但之前是前体无症状的浆细胞性神经症，称为单克隆性γ-不确定意义（MGUS）和闷闷不乐的骨髓瘤（SMM）。尽管有临床风险模型，基因组畸变和成像的可用性，但利用这些指数来准确地对早期阶段前体疾病进行分类和监测临床过程尚未成功。另外，转录组测序的最新进展为将miRNA描述为新型生物标志物提供了新的机会，这可能会大大改变MM分类，管理和治疗的范式。拟议的探索/发育研究的目的是表征有效的肿瘤调节剂肝素酶（HPSE）的作用，而外泌体mircrornas（miRNA）是生物标志物，用于早期检测，分类和进展，从而从无症状前体状态发展MM的MM风险最高的个体。我们将测试血清外泌体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MGU，SMM和MM和MM和MM和性别，年龄，年龄，祖先匹配的对照组的血清中分离出的外泌体中的HPSE蛋白水平； （2）在血清外泌体中进行miRNA分析； （3）确定HPSE相对于骨髓瘤进展而影响外泌体miRNA组成的程度。我们打算利用一个独特的机会，在大型，良好的骨髓瘤人群中探索这些关系，同时利用HPSE和外部生物学生物学和基因组测序的最新进展。我们预计，从这项研究中的发现将是高度信息，并为提出骨髓造成作用的生物学机制以及新的疾病生物标志物提供了必要的基础。这些新型的生物标志物可以显着改变骨髓瘤诊断，分类，管理和治疗的范例，并通过降低与晚期舞台疾病相关的发病率和死亡率来改善总体生存。