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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：
10441549
负责人：
Mikhail Nikiforov
金额：
$ 38.64万
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/10441549
关键词：
Acids 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 resistance Endoplasmic Reticulum Enzymes Fatty Acids Genes Genetic Transcription Glycerol Golgi Apparatus Hematologic Neoplasms Homeostasis Hydro-Lyases Immunoglobulin G Immunoglobulins Inherited Intervention Lipids Lorenzo&apos s oil Maintenance Malignant Neoplasms Mediating Membrane Membrane Lipids Messenger RNA Metabolic Multiple Myeloma Mus Neurons Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Plasma Plasma Cells Play Predisposition 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 clinically relevant efficacy evaluation endoplasmic reticulum stress enzyme biosynthesis experimental study fatty acid biosynthesis lipid metabolism mRNA Expression mouse model novel novel strategies overexpression pharmacologic physical property response screening synergism 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，约占所有血液系统恶性肿瘤的 10%。由于内质网 (ER) 中 IgG 的大量产生，MM 细胞持续承受 ER 应激，被认为是该疾病的“致命弱点”。这一特征使 MM 容易受到加剧的因素的影响内质网应激，如蛋白酶体抑制剂硼替佐米。然而，由于以下原因，目前 MM 对于大多数患者来说是无法治愈的：迅速出现的对蛋白酶体抑制剂的耐药性。因此，新型抗MM药物的鉴定和目标非常重要。相反，内质网蛋白质输出的增加是对内质网应激的适应性反应的一部分。在在当前的应用中，我们提出了一种控制 ER 稳态和耐药性的新型临床相关途径通过调节 ER 膜的鞘脂成分来治疗 MM 中的硼替佐米。我们的初步数据表明这种调节影响 ER 到高尔基体的转运、ER 稳态并最终影响 MM 细胞的活力。此外，我们还鉴定了 3-羟酰基-CoA 脱水酶 (HACD3)，这是一种参与生物合成的酶。极长脂肪酸（VLCFA），作为内质网到高尔基体输出和内质网稳态的重要调节剂。重要的是，HACD3 mRNA 水平在 MM 进展过程中以及来自 MM 患者的 MM 细胞中增加对含硼替佐米的治疗无效。因此，在具体目标 1 中，我们将从功能上描述 VLCFA 依赖的机制 ER 稳态的调节和 HACD3 上游和下游酶的特征这样的监管。在具体目标 2 中，我们将确定调节 MM 细胞中 HACD3 mRNA 表达的机制。在具体目标 3 中，我们将评估 MM 小鼠模型中药物抑制 VLCFA 的功效。