Targeting hexokinase-2 in rheumatoid arthritis

靶向己糖激酶 2 治疗类风湿性关节炎

• 批准号: 10606368
• 负责人: Monica Guma
• 金额: $ 27.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606368
• 关键词: Arthritis; Autoimmune Diseases; Binding; Biological Response Modifier Therapy; Biology; Cartilage; Cells; Combined Modality Therapy; Complement; Data; Development; Disease; Enzymes; Fibroblasts; Glycolysis Inhibition; Grant; Hexokinase 2; Homeostasis; Immunosuppression; Immunotherapy; Impairment; Inflammation; Interleukin-6; Intra-Articular Injections; Joints; Knee; Metabolic; Metabolic Pathway; Metabolism; Miconazole; Mitochondria; Mus; Normal Cell; Oncology; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Protein Isoforms; Research; Rheumatoid Arthritis; Risk; Sampling; Severities; Synovial Cell; Synovial Membrane; Testing; Therapeutic; Thick; Tissues; Translating; Up-Regulation; adenoviral-mediated; arthropathies; bone; cell motility; cell type; extracellular; glucose metabolism; improved; insight; joint destruction; knock-down; macrophage; migration; mutant; novel; novel strategies; novel therapeutics; overexpression; public health relevance; small molecule

PROJECT SUMMARY After several years of research on biological therapies and small molecules to target inflammation, we need a different strategy to further get more insights into mechanisms underlying RA pathogenesis and identify potential new treatments, as a significant proportion of patients are partial responders. In other fields such as oncology the concept of metabolic reprograming to improve immunotherapy are concepts that we truly believe should be translated into autoimmune diseases to complement current therapies. However, there are little data about targeting metabolic changes in RA. We seek with this grant a better understanding of the biology of these metabolic pathways in RA to better characterize a new approach in its therapeutic armamentarium. Our finding that hexokinase 2 (HK2) activity is enhanced only in RA synovium and in different RA synovial cells, suggest a cooperative metabolic reprograming in the joint that contributes to RA development and progression. Our preliminary data demonstrate that while HK1 expression is expressed in both OA and RA synovium, HK2 expression co-localizes with MO and FLS markers, and is only observed in RA and not in OA synovial samples. We also show that HK2 regulates key FLS function as HK2 knockdown impaired FLS invasion. Conversely, HK2 overexpression increases FLS invasion and migration rate. Of note, lactate and PLOD2, which are involved in cell migration and invasion, are upregulated after HK2 expression. Up-regulation of extracellular lactate also suggests a metabolic shift towards accelerated glycolytic metabolism. An HK2 mutant lacking its mitochondrial- binding motif (HK2ΔN) reversed the invasive phenotype. In MO, a peptide that dissociates HK2 from mitochondria, impaired IL-6 secretion. Importantly, adenovirus-mediated expression of HK2 in the knee by intra- articular injection induced synovial thickness, which was much less evident when HK2ΔN was intra-articular injected. Finally, HK2F/F-Col1a1 mice, which deletes HK2 in FLS among other non-hematopoietic cells, and treatment with clotrimazole, which dissociated HK2 from mitochondria, significantly decreased arthritis severity. Thus, we will test the hypothesis that mitochondrial HK2 is key regulator of FLS phenotype and MO activation, which contributes to joint destruction in RA. The identification of HK2, an isoform-specific contributor to elevated cell glucose metabolism in RA synovial tissue offers a safer approach than global glycolysis inhibition. HK2 could be selectively targeted without compromising systemic homeostasis or corresponding metabolic function in normal cells as a novel additional approach for combination therapy in RA joint disease independent of systemic immunosuppression.

项目摘要 经过数年的生物疗法和小分子进行靶向注射的研究，我们需要一个 不同的策略，以进一步了解RA发病机理的机制并确定潜力 新疗法，因为很大一部分患者是部分反应者。在其他领域，例如肿瘤学 代谢重编程以改善免疫疗法的概念是我们真正相信应该是的概念 转化为自身免疫性疾病以补充当前疗法。但是，几乎没有关于 靶向RA代谢变化。我们寻求这项赠款对这些生物的生物学有更好的了解 RA中的代谢途径可以更好地表征其治疗性武术中的新方法。我们的发现 己糖激酶2（HK2）的活性仅在RA滑膜和不同的RA滑膜细胞中得到增强，这表明 关节中的合作代谢重编程有助于RA的发展和进展。我们的 初步数据表明，虽然HK1表达在OA和RA Synovium中均表达，但HK2 表达与MO和FLS标记共定位，仅在RA中观察到，而不是在OA滑膜样品中观察到。 我们还表明，HK2调节关键FLS功能是HK2敲低的FLS入侵。相反，HK2 过表达增加了FL侵袭和迁移率。值得注意的是，涉及 细胞迁移和入侵在HK2表达后会更新。细胞外乳酸的上调 表明代谢向加速糖酵解代谢的转变。缺乏线粒体的HK2突变体 结合基序（HK2ΔN）逆转了侵入性表型。在Mo中，将HK2解离的胡椒 线粒体，IL-6分泌受损。重要的是，腺病毒介导的HK2在膝盖中的表达 关节注射诱导的滑膜厚度，当HK2ΔN为关节内时，这是较少的证据 注射。最后，HK2F/F-COL1A1小鼠，在其他非山摩托式细胞中删除HK2，并且 用线粒体解散HK2的克替妥唑的治疗显着提高了关节炎的严重程度。 这是我们将测试线粒体HK2是FLS表型和MO激活的关键调节剂的假设， 这有助于RA的联合破坏。 HK2的识别，这是同等同工型的特定贡献者 RA滑膜组织中的细胞葡萄糖代谢升高提供了一种比全球糖酵解更安全的方法 抑制。 HK2可以选择性地靶向，而无需妥协全身稳态或 正常细胞中的相应代谢功能是一种新型的组合方法 RA联合疾病的治疗与全身免疫抑制无关。