Prevention of MGUS Progression to MM by Modulating the Bone Marrow Microenvironment

通过调节骨髓微环境预防 MGUS 进展为 MM

基本信息

批准号：
10745012
负责人：
FENGHUANG ZHAN
金额：
$ 29.04万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745012
关键词：
Acceleration Age Aging Automobile Driving Biological Markers Biology Bone Marrow CDKN2A gene Cell Aging Cell Proliferation Cells Cellular Metabolic Process Cellular biology Cessation of life Chromosomal translocation Chromosome 14 Cytometry DNA Data Development Disease Ectopic Expression Elderly Excision Ganciclovir Gene Expression Genetic Goals Growth Growth Factor Hematopoietic Neoplasms Human IGH@ gene cluster Immune Immunoglobulin A Immunoglobulin G Immunoglobulins Immunologic Surveillance Immunosuppression Interleukin-6 Iron Lesion Light Link Longevity Lytic Macrophage Malignant Neoplasms Molecular Molecular Abnormality Molecular Target Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Patients Persons Phenotype Plasma Cells Play Population Prevalence Prevention Proteins Risk Factors Role Sampling Signal Pathway T-Lymphocyte Testing Transgenic Mice Transgenic Organisms Work bone cancer prevention cell growth cellular targeting cytokine design high risk human monoclonal antibodies iron metabolism luminescence mouse model neoplastic cell novel novel strategies novel therapeutic intervention premalignant prevent secretory protein senescence single-cell RNA sequencing tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY The long-term objective of this work is to determine the functional role of the bone marrow microenvironment in regulating the plasma cell growth of monoclonal gammopathy of undetermined significance (MGUS), using multiple MGUS mouse models to define reliable biomarkers. Our findings should form the basis for designing novel treatment approaches to prevent MGUS progression to multiple myeloma (MM). MGUS is a precancerous, but clonal condition with aberrant DNA changes in plasma cells (PC). The prevalence of MGUS increases with age. It is 3.2% at 50 years but rises to 9% for those older than 85, suggesting that risk factors associated with aging play an important role in MGUS development. MGUS may progress to smoldering multiple myeloma (SMM) and/or to MM, requiring therapy. Therefore, it is particularly important to identify and subsequently target the risk factors associated with MGUS progression. By studying MGUS mouse models and primary human samples from MGUS patients, we have demonstrated that bone marrow cellular senescence related to aging, iron metabolism, and increased DKK1 in MGUS plasma cells are linked to MGUS progression. We hypothesize that changes in the bone marrow microenvironment (ME) alter gene expression of MGUS plasma cells and induce both bone destruction and immunosuppression resulting in MGUS plasma cell proliferation and disease escape from effective immune surveillance. We propose three specific aims to prove this hypothesis: (1) determine the role of cellular senescence of ME in MGUS progression; (2) determine the role of DKK1 in promoting MGUS progression in adoptive transgenic mice; and (3) determine cellular and molecular mechanisms of MGUS progression. Our goal is to discover novel therapeutic approaches to prevent human MGUS progression.

项目概要这项工作的长期目标是确定骨髓微环境的功能作用在调节意义未明的单克隆丙种球蛋白病（MGUS）的浆细胞生长中，使用多个 MGUS 小鼠模型来定义可靠的生物标志物。我们的发现应该成为设计的基础预防 MGUS 进展为多发性骨髓瘤 (MM) 的新治疗方法。 MGUS 是一种癌前病变，但浆细胞 (PC) 中 DNA 发生异常变化的克隆状态。 MGUS 的患病率随年龄。 50 岁时这一比例为 3.2%，但 85 岁以上的人群中这一比例上升至 9%，这表明与衰老在 MGUS 的发展中起着重要作用。 MGUS 可能进展为冒烟型多发性骨髓瘤 (SMM) 和/或 MM，需要治疗。因此，识别并随后瞄准目标尤为重要。与 MGUS 进展相关的危险因素。通过研究 MGUS 小鼠模型和原代人类来自 MGUS 患者的样本，我们证明骨髓细胞衰老与衰老相关，铁代谢和 MGUS 浆细胞中 DKK1 的增加与 MGUS 进展有关。我们假设骨髓微环境（ME）的变化改变了 MGUS 浆细胞的基因表达，诱导骨质破坏和免疫抑制，导致 MGUS 浆细胞增殖和疾病逃避有效的免疫监视。我们提出三个具体目标来证明这一假设：(1) 确定 ME 细胞衰老在 MGUS 进展中的作用； (2)确定DKK1的作用促进收养转基因小鼠的 MGUS 进展； (3) 确定细胞和分子机制 MGUS 进展。我们的目标是发现预防人类 MGUS 的新治疗方法进展。