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THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA

硒蛋白合成途径在急性髓系白血病中的作用

基本信息

批准号：
10659193
负责人：
Daisuke Nakada
金额：
$ 45.55万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659193
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Affect Age Amino Acids Anabolism Animal Model Antioxidants Attenuated Binding Bioinformatics Biological Assay CRISPR screen CRISPR/Cas technology Cell Death Cell Line Cells Clustered Regularly Interspaced Short Palindromic Repeats Codon Nucleotides Coupled Data Databases Dedications Dependence Diet Diet therapy Dietary Selenium Dropout Drug Metabolic Detoxication Enhancers FLT3 gene Gene Deletion Genes Hand Hematopoiesis Homeostasis Human Knockout Mice Lipid Peroxidation Lipid Peroxides MLL-AF9 Maintenance Malignant Neoplasms Metabolic Metabolism Modeling Mus Mutation Organism Oxidation-Reduction Oxidative Stress Pathway interactions Patients Production Prognosis Regulation Role Sampling Selenium Selenocysteine Testing Therapeutic Trace Elements Translations Transplantation Xenograft procedure acute myeloid leukemia cell attenuation chemotherapy combinatorial conditional knockout dietary dietary manipulation feeding genetic analysis genetic approach glutathione peroxidase improved in vivo insight interest leukemia treatment leukemogenesis mouse model novel novel strategies novel therapeutics older patient patient derived xenograft model polypeptide protein expression selenium deficiency selenoprotein therapeutic target thioredoxin reductase transcription factor whole genome

项目摘要

AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. Using a bioinformatics approach and a whole-genome CRISPR screening approach, we identified regulators of selenium metabolism to be important for AML survival. Selenium is required for cells to synthesize selenocysteine, which is then used to produce selenoproteins. Since many selenoproteins are involved in redox regulation, we hypothesized that selenium metabolism is required for redox maintenance of AML. This hypothesis will be tested in the following three aims. In aim 1, we will use mouse models that we have generated that have mutations in the genes we identified in the CRISPR screen to examine the requirement of selenium metabolism in murine AML. In aim 2, we will use a mouse model that lacks the redox regulator, which we hypothesize to be downstream of the selenium metabolism pathway, to examine how this redox regulator promotes murine AML. In aim 3, we will study the mechanisms we discovered in human AML patient-derived xenograft models to examine the therapeutic potential of inhibiting selenium metabolism in AML. These genetic analyses with both murine and human AML models should bring novel insights into how AML regulates selenium metabolism and the therapeutic potential of targeting this mechanism.

急性髓系白血病是成人最常见的急性白血病，且随年龄增长而增多。尽管总体上白血病治疗的进步，急性髓细胞白血病对老年患者的预后仍然是毁灭性的(更少超过10%的患者存活5年)。因此，治疗AML的新疗法是必要的。使用生物信息学方法和全基因组CRISPR筛选方法，我们确定了硒代谢的调节因子对急性髓系白血病的生存至关重要。硒是细胞合成硒半胱氨酸所必需的，然后使用来生产硒蛋白。由于许多硒蛋白参与氧化还原调节，我们假设硒代谢是急性髓系白血病氧化还原维持所必需的。这一假设将在以下方面得到检验三个目标。在目标1中，我们将使用我们产生的具有基因突变的小鼠模型在CRISPR筛查中鉴定，以检查小鼠急性髓细胞白血病对硒代谢的需求。在目标2中，我们将使用一个没有氧化还原调节器的小鼠模型，我们假设它在硒代谢途径，以研究这种氧化还原调节因子如何促进小鼠急性髓系白血病。在《目标3》中，我们将研究我们在人类AML患者来源的异种移植模型中发现的机制，以检查抑制急性髓系白血病患者硒代谢的治疗潜力。这些对小鼠和小鼠的遗传分析人类AML模型应该为AML如何调节硒代谢和靶向这一机制的治疗潜力。