Elucidation of the mechanism of disease of VEXAS Syndrome

阐明VEXAS综合征的发病机制

基本信息

批准号：
10752251
负责人：
Samuel James Magaziner
金额：
$ 5.27万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752251
关键词：
Ablation Accounting Address Adrenal Cortex Hormones Affect Age Automobile Driving Biological Biological Models Bone Marrow Bone Marrow Diseases Cell Culture Techniques Cell Death Cell Line Cell model Cells Charge Chinese Hamster Clonal Expansion Clonal Hematopoietic Stem Cell Complementary DNA Cytoplasm Data Defect Degradation Pathway Disease Disease Progression Disparate Dose Dysmyelopoietic Syndromes Elderly Endoplasmic Reticulum Enzymes Future Genes Health Hematological Disease Hematology Hematopoietic stem cells Homeostasis Human Immune Inflammation Inflammatory Investigation Link Lymphocyte Malignant Neoplasms Mediating Methionine Modeling Molecular Target Mutation Myelogenous Myeloid Cells Neurodegenerative Disorders Nuclear Ovary Pancytopenia Pathogenesis Pathway interactions Patients Phenotype Process Protein Isoforms Proteins Proteomics Regulation Relapsing polychondritis Residual state Role Site Syndrome Temperature Testing Therapeutic Therapeutic Intervention Transgenic Organisms Translating Translations U937 Cells UBE2G2 gene Ubiquitin-Activating Enzymes Ubiquitin-Conjugating Enzymes Vacuole Validation Variant Vasculitis X Chromosome autoinflammatory autoinflammatory diseases cytokine male men molecular targeted therapies monocyte mortality mutant novel response small hairpin RNA small molecule small molecule inhibitor transcriptomics ubiquitin ligase ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Elucidation of a newly characterized clonal bone marrow and autoinflammatory disease, VEXAS Syndrome, prompts re-examination of the master regulator of ubiquitylation, UBA1. VEXAS stands for Vacuoles, E1, X- linked, Autoinflammatory, Somatic syndrome and presents with disparate inflammatory (e.g. relapsing polychondritis, vasculitides) and hematologic (e.g. pancytopenia, myelodysplastic syndrome) conditions. The disease is present in 1:4000 men over the age of 50 and has a 40% mortality rate. Current therapeutic treatment is limited to high dose corticosteroids. In affected patients, acquired or somatic variants in the UBA1 gene are present in hematopoietic stem cells (HPSCs) and become lineage restricted to myeloid cells. VEXAS presents primarily in elderly males as UBA1 is located on the X-chromosome. UBA1 encodes the primary ubiquitin (Ub) activating enzyme (E1), accounting for over 97% of all downstream ubiquitylation. Protein ubiquitylation occurs via a tightly regulated enzymatic cascade where sequential activation of E1 to Ub-conjugating enzyme (E2) to Ub-ligase (E3) enzymes ultimately leads to substrate ubiquitylation. Prior studies have predominantly focused on the role of E3 ligases in disease progression due to their protein-specific targeting in ubiquitylation. Far less is known regarding the role of UBA1 in disease pathogenesis. Notably, VEXAS highlights the importance of UBA1 in maintaining immune homeostasis and driving clonal blood disease. Through transcriptomic and cytokine profiling approaches, our group has identified mutant myeloid cells as the primary drivers of inflammation although the underlying mechanism remains unclear. Here I propose to determine the mechanism of VEXAS using unbiased approaches. Despite UBA1 mutation present in HSPCs, the mutation is lineage restricted to myeloid cells and absent in lymphocytes. Our preliminary results utilizing a temperature sensitive cell line (Chinese Hamster Ovary [CHO] line ts20) suggests VEXAS mutant UBA1 fails to charge the cognate E2s of the endoplasmic reticulum associated degradation pathway (ERAD), UBE2J1 and UBE2G2, potentially upregulating the unfolded protein response (UPR). These findings suggest that inappropriate UBA1 expression may both drive disease in VEXAS and allow selective clonal expansion of a pro-inflammatory myeloid lineage as potentiated by specific downstream effectors possibly linked to ERAD and UPR. In this study I propose to 1) perform an unbiased delineation of novel effectors driving UBA1-dependent inflammation pathways and 2) functionally validate effectors identified through model systems and unbiased approaches through a combination of small molecule, biologic, and transgenic approaches. My combined studies will not only be important for elucidating the mechanism of disease and treatment in VEXAS but may also apply to a wider understanding of key cellular ubiquitylation processes, autoinflammatory disease, and bone marrow-derived diseases.

项目摘要阐明新特征的克隆骨髓和自发性疾病，Vexas综合征，提示重新检查泛素化总体调节器UBA1。 Vexas代表液泡，E1，X- 链接，自身炎症，体细胞综合征和具有不同炎症的呈现（例如复发多层炎，血管炎）和血液学（例如全年型，骨髓增生综合征）。这疾病以50岁以上的1：4000名男性存在，死亡率为40％。当前的治疗治疗仅限于高剂量皮质类固醇。在受影响的患者中，UBA1基因的获得或体细胞变异是存在于造血干细胞（HPSC）中，并依赖于髓样细胞的谱系。 vexas礼物 uba1主要位于X染色体上，主要是在老年男性中。 UBA1编码主要的泛素（UB）激活酶（E1），占所有下游泛素化的97％以上。蛋白质泛素化发生通过严格调节的酶级联 UB - 岩石酶（E3）酶最终导致底物泛素化。先前的研究主要集中关于E3连接酶在疾病进展中的作用，由于其蛋白质特异性靶向在泛素化中。少得多关于UBA1在疾病发病机理中的作用已知。值得注意的是，Vexas强调了 UBA1维持免疫稳态和驱动克隆血液疾病。通过转录组和细胞因子分析方法，我们的小组已将突变的髓样细胞确定为炎症的主要驱动因素尽管基本机制尚不清楚。在这里，我建议确定Vexas的机制使用公正的方法。尽管HSPC中存在UBA1突变，但该突变仍仅限于髓样细胞，淋巴细胞不存在。我们利用温度敏感细胞系的初步结果（中国仓鼠卵巢[CHO]系TS20）表明Vexas突变体UBA1无法充电内质网相关降解途径（ERAD），UBE2J1和UBE2G2，可能会上调展开的蛋白质反应（UPR）。这些发现表明不适当的UBA1表达可能既可能在Vexas中驱动疾病，并允许选择性克隆膨胀促炎性髓样谱系由特定的下游效应子启动，可能与Erad和UPR相关。在这项研究中，我建议1）对驱动UBA1依赖性炎症途径的新型效应子进行公正的描述，2）通过模型系统和无偏方法识别的功能验证效应子小分子，生物学和转基因方法。我的合并研究不仅对阐明Vexas疾病和治疗机制，但也可能适用于对关键的细胞泛素化过程，自发性疾病和骨髓衍生的疾病。