ENVIRONMENT & GENETICS OF MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (MGUS)

环境

基本信息

批准号：
8321967
负责人：
MICHAEL H TOMASSON
金额：
$ 19.75万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321967
关键词：
African American Age Antibodies Antibody Formation Ascaridil Bone Density Chromosomal translocation Clinic Computer software DNA Data Data Set Development Diet Dimensions Disease Disease Progression Dose Electrophoresis Environment Environmental Risk Factor Enzyme-Linked Immunosorbent Assay Family member First Degree Relative Fracture Frequencies Genes Genetic Genome Scan Genotype Goals Heavy-Chain Immunoglobulins Human IgG1 IgG3 Immunization Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Isotypes Immunoglobulin M Immunoglobulins Individual Inherited Ionizing radiation Light-Chain Immunoglobulins Malignant Neoplasms Maps Modeling Monoclonal Gammapathies Monoclonal gammopathy of uncertain significance Mouse Strains Multiple Myeloma Mus Osteoporosis Patients Persons Phenotype Plasma Cells Predisposition Premalignant Prevention strategy Production Protocols documentation Quantitative Trait Loci Resistance Risk Sampling Screening procedure Serum Serum Proteins Somatic Mutation Testing Thrombosis Time Two-Dimensional Gel Electrophoresis Universities Vitamin D Vitamin D Deficiency Washington base deprivation genetic variant genome wide association study human disease insight research study response

项目摘要

DESCRIPTION (provided by applicant): Monoclonal gammopathy of uncertain significance (MGUS) is a common, pre-malignant plasma cell disorder found in 3.2 and 5.3 percent of individuals over the ages of 50 and 70 years respectively (Kyle RA, NEJM, 2006). MGUS is characterized by monoclonal serum immunoglobulin, an increased risk of thrombosis, an increased risk of osteoporosis and bone fractures and a risk of developing malignancy (predominantly multiple myeloma at 1% per year (REFS Kyle RA, NEJM, 2002). MGUS has a significant component of inherited risk, and is found at 2-3 fold higher rates in African Americans, and 2-fold higher rates in family members of MGUS patients. Neither the genetic basis nor the environmental factors contributing to MGUS/MM risk have been defined. Our long-term goal is to develop screening and prevention strategies based on a detailed understanding of MGUS/MM genetics. The C57BL/KaLwRij (KaLwRij) mouse strain, described decades ago (Radl J, Clin Exp Immunol, 1984), develops MGUS at high frequency with many of the same features of the human disease including an increased risk of developing MM. Since the most common somatic mutations to occur in MGUS/MM are chromosomal translocations involving immunoglobulin heavy chain switch regions, our hypothesis is that germline susceptibility to MGUS is the consequence of abnormal immunoglobulin isotype switching. We found highly significant differences in antibody isotype responses by ELISA between KaLwRij and 11 separate mouse strains. We also found that ionizing radiation and vitamin D deprivation, two environmental factors associated with MM, induced significant and strain-specific changes in antibody responses in mice. To advance our understanding of MGUS/MM risks, we propose: Specific Aim 1: Characterize effects of ionizing radiation, vitamin D deprivation and strain background on immunoglobulin isotype responses and monoclonal gammopathy (MGUS) development in mice; Specific Aim 2: Map quantitative trait loci (QTL) for MGUS/MM risk and identify somatic mutations associated with disease progression. The experiments in SA1 will provide valuable insights into the effects of strain and relevant environmental factors to MGUS development. The experiments in SA2 will provide an MGUS-specific QT data set and matched DNA samples that will allow us to identify QTL's in mice associated with MGUS risk. These mice will be used as a platform to explore the relationship between inherited MGUS risk and environmental factors and the data we generate will inform ongoing genome-wide association (GWA) studies in humans (a collaborative effort between Washington University and the Mayo Clinic). This project will be part of a coordinated effort to identify the genetic factors that drive MGUS and MM in humans.

描述（由申请人提供）：意义不明的单克隆丙种球蛋白病 (MGUS) 是一种常见的癌前浆细胞疾病，在 50 岁和 70 岁以上的个体中分别有 3.2% 和 5.3% 的人发现（Kyle RA，NEJM，2006）。 MGUS 的特点是单克隆血清免疫球蛋白、血栓形成风险增加、骨质疏松和骨折风险增加以及发生恶性肿瘤的风险（主要是多发性骨髓瘤，每年 1%）（REFS Kyle RA，NEJM，2002）。MGUS 具有MGUS 是遗传风险的重要组成部分，非裔美国人的发病率高出 2-3 倍，MGUS 家庭成员的发病率高出 2 倍导致 MGUS/MM 风险的遗传基础和环境因素均尚未确定。我们的长期目标是根据对 C57BL/KaLwRij (KaLwRij) 遗传学的详细了解制定筛查和预防策略。数十年前描述的小鼠品系（Radl J，Clin Exp Immunol，1984），以高频率发生 MGUS，具有许多与人类疾病相同的特征，包括发生 MM 的风险增加。 MGUS/MM 中最常见的体细胞突变是涉及免疫球蛋白重链转换区域的染色体易位，我们的假设是种系对 MGUS 的易感性是异常免疫球蛋白同种型转换的结果。通过 ELISA，我们发现 KaLwRij 和 11 种不同的小鼠品系之间的抗体同种型反应存在高度显着差异。我们还发现，电离辐射和维生素 D 缺乏这两种与多发性骨髓瘤相关的环境因素会引起小鼠抗体反应的显着且菌株特异性的变化。为了加深我们对 MGUS/MM 风险的理解，我们提出：具体目标 1：表征电离辐射、维生素 D 缺乏和菌株背景对小鼠免疫球蛋白同种型反应和单克隆丙种球蛋白病 (MGUS) 发展的影响；具体目标 2：绘制 MGUS/MM 风险的数量性状位点 (QTL) 并识别与疾病进展相关的体细胞突变。 SA1 中的实验将为了解菌株和相关环境因素对 MGUS 发育的影响提供有价值的见解。 SA2 中的实验将提供 MGUS 特异性 QT 数据集和匹配的 DNA 样本，使我们能够识别与 MGUS 风险相关的小鼠中的 QTL。这些小鼠将被用作探索遗传性 MGUS 风险与环境因素之间关系的平台，我们生成的数据将为正在进行的人类全基因组关联 (GWA) 研究（华盛顿大学和梅奥诊所之间的合作项目）提供信息。该项目将成为识别驱动人类 MGUS 和 MM 的遗传因素的协调努力的一部分。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Germinal center B-cells resist transformation by Kras independently of tumor suppressor Arf.

生发中心 B 细胞抵抗 Kras 的转化，独立于肿瘤抑制因子 Arf。

DOI：
发表时间：
2013
期刊：
影响因子：
3.7
作者：
Mullins, Chelsea D;Su, Mack Y;Hucthagowder, Vishwanathan;Chu, Liang;Lu, Lan;Kulkarni, Shashikant;Novack, Deborah;Vij, Ravi;Tomasson, Michael H
通讯作者：
Tomasson, Michael H