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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.

AML是成人中最常见的急性白血病，并且随着年龄的增长而增加。尽管整体