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Regulation and Function of Very Long Chain Fatty Acid Biosynthesis in Multiple Myeloma

多发性骨髓瘤中极长链脂肪酸生物合成的调控和功能

基本信息

批准号：
10560857
负责人：
Mikhail Nikiforov
金额：
$ 39.12万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560857
关键词：
Adrenoleukodystrophy Affect Anabolism Antineoplastic Agents Aryl Hydrocarbon Receptor Binding Blood Bortezomib Cell Survival Cell membrane Cells Ceramides Cessation of life Chromosomal translocation Coenzyme A Data Disease Drug Targeting Drug resistance Endoplasmic Reticulum Enzymes Fatty Acids Genes Genetic Transcription Glycerol Golgi Apparatus Heel Hematologic Neoplasms Hematology Homeostasis Hydro-Lyases Immunoglobulin G Immunoglobulins Inherited Intervention Lorenzo&apos s oil Maintenance Malignant Neoplasms Mediating Membrane Membrane Lipids Messenger RNA Metabolic Multiple Myeloma Mus Neurons Pathway interactions Patients Pharmacology Phosphotransferases Plasma Plasma Cells Play Production Property Proteasome Inhibitor Protein Export Pathway Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Refractory Regulation Reporting Resistance Resistance development Risk Role Signal Transduction Sphingolipids Testing Therapeutic Effect Time Transcriptional Activation Transcriptional Regulation Transgenic Organisms Very Long Chain Fatty Acid Xenograft procedure base clinically relevant efficacy evaluation endoplasmic reticulum stress enzyme biosynthesis experimental study fatty acid biosynthesis lipid metabolism mRNA Expression mouse model novel novel strategies overexpression physical property response screening therapy resistant transcription factor

项目摘要

Multiple Myeloma (MM) is a plasma cell disorder that accounts for ~10% of all hematologic malignancies. Due to high production of IgG in endoplasmic reticulum (ER), MM cells continuously undergo ER stress which is considered an “Achille’s heel” of the disease. This feature makes MM susceptible to the agents that exacerbate ER stress, such as proteasome inhibitor bortezomib. Yet, currently MM is incurable for most patients due to rapidly emerging resistance to proteasome inhibitors. Therefore, identification of novel anti-MM drugs and targets is of high importance. Conversely, an increase in protein export from ER is a part of the adaptive response to ER stress. In the current application, we propose a novel clinically relevant pathway controlling ER homeostasis and resistance to bortezomib in MM via modulation of sphingolipid composition of the ER membrane. Our preliminary data suggest that such modulation affects ER-to-Golgi transport, ER homeostasis and ultimately MM cell viability. Furthermore, we identified 3-hydroxyacyl-CoA dehydratases (HACD3), an enzyme involved in the biosynthesis of very long fatty acids (VLCFA), as an important regulator of ER-to-Golgi export and ER homeostasis. Importantly, HACD3 mRNA levels were increased during MM progression and in MM cells from MM patients refractory to bortezomib-containing therapy. Therefore, in Specific Aim 1, we will functionally characterize mechanisms underlying VLCFA-dependent regulation of ER homeostasis and characterize enzymes upstream and downstream of HACD3 responsible for such regulation. In Specific Aim 2, we will identify mechanisms regulating HACD3 mRNA expression in MM cells. In Specific Aim 3, we will evaluate the efficacy of pharmacological suppression of VLCFAs in MM mouse models.

多发性骨髓瘤（MM）是一种浆细胞疾病，约占所有血液恶性肿瘤的10%。