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Mechanism of gp96/grp94 in regulating plasma cells and myeloma

gp96/grp94调节浆细胞与骨髓瘤的机制

基本信息

批准号：
10250692
负责人：
Bei Liu
金额：
$ 26.87万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250692
关键词：
Address Antibody Formation B-Cell Activation B-Lymphocytes Binding Proteins Biology Biometry Bortezomib Cell Compartmentation Cell Line Cell Survival Cell physiology Cells Cellular biology Chronic Clinical Collaborations Data Development Disease Doxorubicin Drug resistance Endoplasmic Reticulum Ensure Factor X Genetic Genetic Transcription Genetic study Growth Heat shock proteins Heat-Shock Proteins 90 Hematology Human Institutes Integrins Knockout Mice Lead Link Low Density Lipoprotein Receptor Malignant - descriptor Mature B-Lymphocyte Mediating Modeling Molecular Molecular Chaperones Multiple Myeloma Mus Oncology Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Plasma Cell Neoplasm Plasma Cells Proteasome Inhibitor Proteins Quality Control RNA Splicing Research Personnel Resistance Role Signal Pathway Signal Transduction System Therapeutic Toll-like receptors Transgenic Mice Transgenic Organisms Treatment Efficacy Variant WNT Signaling Pathway Work addiction anticancer research beta catenin genetic regulatory protein inhibitor/antagonist insight lipoprotein receptor-related protein 6 mouse model new therapeutic target novel overexpression plasma cell differentiation preclinical efficacy public health relevance response small molecule success survivin targeted treatment tool transcription factor transcription factor USF

项目摘要

DESCRIPTION (provided by applicant): This study addresses the key roles of grp94, a major molecular chaperone in the endoplasmic reticulum (ER) in plasma cell biology and multiple myeloma (MM). MM is an incurable plasma cell neoplasm whose pathogenesis is closely linked to dysregulated unfolded protein response (UPR) in the ER. Constitutive activation of UPR in mice, as demonstrated by transgenic expression of a master UPR transcription factor XBP1s (a UPR-specific splice variant of X-box binding protein 1), causes myeloma. However, the underlying mechanism remains unknown. We have demonstrated that grp94 is an obligate chaperone for Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6). Furthermore, the persistence of plasma cells, as well as the development of myeloma in XBP1s-transgenic mice is critically dependent on grp94. The addiction of myeloma cells to grp94 was also demonstrated genetically and pharmacologically using multiple human myeloma cell lines. Furthermore, we found that grp94 is highly expressed in malignant plasma cells in MM. The higher level of grp94 is significantly associated with a worse clinical stage in MM. Thus, we hypothesize that the pathogenesis of MM is driven by both dysregulated UPR and canonical Wnt signaling, both of which converges onto grp94. We will address this hypothesis in Specific Aim 1, by taking advantage of multiple unique genetic tools we have generated including B cell-specific grp94 knockout mice and B cell-specific β-catenin knockout mice. In Specific Aim 2, we will determine the roles of grp94 in the full clinical manifestation of myeloma in both novel MM mouse models and xenogenic human myeloma model. Moreover, in collaboration with Dr. Gabriela Chiosis from Sloan-Kettering Institute for Cancer Research, a novel class of grp94-specific inhibitors will be developed and investigated for their preclinical efficacy against myeloma. Overall, our studies will not only provide fundamental new insights into the roles of grp94 in the pathogenesis of MM, but also be instrumental in the development of grp94-targeted therapeutics against this disease.