Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma

认证基因工程临床相关的多发性骨髓瘤小鼠模型

基本信息

批准号：
10310482
负责人：
Marta Chesi
金额：
$ 37.21万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-07 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310482
关键词：
Address Amino Acid Sequence Anemia B-Lymphocytes Bacterial Artificial Chromosomes Binding Biological Biological Models Biology Bone Diseases Bone Marrow Cell Line Cell Survival Cell Transplantation Cells Clinical Combination Drug Therapy Combined Modality Therapy Complex Credentialing Dependence Drug Receptors Drug resistance Drug usage Engineering Generations Genes Genetic Genetic Engineering Genomic approach Glucocorticoids Goals Hematologic Neoplasms Home Human Human Characteristics Immune system Immunocompetent Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulins Immunomodulators Immunotherapy Impairment Indolent Interferon Type II Kidney Mediating Modeling Monoclonal gammopathy of uncertain significance Multiple Myeloma Mus Mutation Newly Diagnosed Patients Pharmaceutical Preparations Population Pre-Clinical Model Precancerous Conditions Predictive Value Proteasome Inhibitor Publishing Refractory Regulatory Element Relapse Research Personnel Resistance Role Splenocyte Structure of germinal center of lymph node T-Cell Proliferation Thalidomide Transcription Factor 3 Transgenic Mice Transplantation Ubiquitin Validation Variant Vertebral column Work clinical practice clinical predictors clinically relevant drug-sensitive experimental study gene product genetic manipulation human disease in vivo in vivo Model lenalidomide mouse model neoplasm immunotherapy neoplastic cell novel plasma cell differentiation pleiotropism pomalidomide post-transplant receptor recruit relapse patients response tumor tumor immunology tumor progression

项目摘要

Project Summary/Abstract Thalidomide (Thal) and its derivatives, Lenalidomide (Len) and Pomalidomide (POM), are immune modulatory drugs (IMiDs) used in the treatment of multiple myeloma (MM) and few other hematological malignancies. Although they represent the backbone treatment for both newly diagnosed and relapse/refractory MM patients, their clinical use remains mostly empirical because of lack of suitable in vivo model systems to study their complex mechanisms of action. Murine cells are intrinsically resistant to IMiDs because of different amino acid sequence in the IMiD binding domain of cereblon (CRBN). By building upon our extensively validated Vk*MYC transgenic mouse model of MM, we have generated a novel transgenic mouse, Vk*MYChCRBN, expressing the full human CRBN (hCRBN) gene under the control of its endogenous regulatory elements, rendering it IMiD sensitive. As previously done for the Vk*MYC model, we will extensively characterize the new Vk*MYChCRBN model and will use it to understand the IMiD effects on the tumor and the immune system with the ultimate goal to inform clinical practice.

项目摘要/摘要沙利度胺（thal）及其衍生物，Lenalidomide（Len）和Pomalidomide（POM）是免疫的用于治疗多发性骨髓瘤（MM）的调节药物（IMID）和其他少数其他血液学恶性肿瘤。尽管它们代表了两者的骨干治疗被诊断和复发/难治性的MM患者，其临床用途主要是经验的缺乏适合研究其复杂作用机理的体内模型系统。鼠细胞是由于在IMID结合结构域中具有不同的氨基酸序列，因此对IMID具有本质上的抗性 Cereblon（CRBN）。通过在我们经过广泛验证的VK*MYC转基因鼠标模型上构建 MM，我们产生了一种新颖的转基因老鼠VK*Mychcrbn，表达了完整的人类CRBN （HCRBN）基因在其内源性调节元件的控制下，使其具有敏感性。与以前为VK*MYC模型所做的那样，我们将广泛地描述新的VK*mychcrbn 模型并将使用它来了解对肿瘤和免疫系统的影响为临床实践提供信息的最终目标。