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：
10317554
负责人：
Mikhail Nikiforov
金额：
$ 38.43万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317554
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，占所有血液癌的约10％。由于IgG在内质网（ER）中的高产生，MM细胞不断经历ER应激，被认为是这种疾病的“ achille的脚跟”。此功能使MM容易受到加剧的代理 ER应激，例如蛋白酶体抑制剂硼替佐米。但是，由于大多数患者的MM目前无法治愈对蛋白酶体抑制剂的耐药性迅速。因此，鉴定新型抗MM药物和目标非常重要。相反，从ER导出的蛋白质增加是对ER应激的自适应反应的一部分。在当前的应用，我们提出了一种临床上相关的新型途径，以控制ER的稳态和阻力通过调节ER膜的鞘脂组成，以在MM中的硼替佐米。我们的初步数据表明这种调节会影响ER到高尔基体的运输，ER稳态和最终MM细胞活力。此外，我们确定了3-羟基酰基-COA脱水酶（HACD3），这是一种参与生物合成的酶长长的脂肪酸（VLCFA）是ER到高尔基体出口和ER稳态的重要调节剂。重要的是，在MM进展过程中和MM患者的MM细胞中HACD3 mRNA水平升高对含硼替佐米的耐药疗法难治性。因此，在特定的目标1中，我们将在功能上表征依赖VLCFA的机制 ER稳态的调节并表征HACD3上游和下游的酶负责这样的调节。在特定的目标2中，我们将确定调查MM细胞中HACD3 mRNA表达的机制。在特定的目标3中，我们将评估MM小鼠模型中VLCFA的药物抑制的有效性。