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PI3 Kinase Inactivation in Myelodysplastic Syndrome

骨髓增生异常综合征中的 PI3 激酶失活

基本信息

批准号：
10518821
负责人：
Kira Gritsman
金额：
$ 51.86万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2022-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10518821
关键词：
1-Phosphatidylinositol 3-Kinase Abnormal Cell Affect Alternative Splicing Animal Model Arginine Autophagocytosis Biological Models Cells Clinical Cytokine Signaling DNA Damage Data Data Set Defect Dependence Development Disease Dysmyelopoietic Syndromes Dysplasia Event Exons Gene Expression Gene Expression Profile Genes Genomic Instability Growth Factor Hematopoiesis Hematopoietic Hematopoietic Cell Growth Factors Hematopoietic stem cells Hemorrhage Human Impairment Infection Knock-out Knockout Mice Lead Link Lipids Maintenance Messenger RNA Metformin Modeling Mus Mutation Myelogenous Nuclear PTEN gene Pathogenesis Pathway interactions Patients Pattern Persons Pharmacology Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Process Protein Isoforms Protein Kinase Proteins Proto-Oncogene Proteins c-akt Quality Control RNA Splicing RNA-Binding Proteins Recycling Reporting Role SRSF2 gene Sampling Serine Signal Transduction Spliceosomes Testing Therapeutic Transfusion aging population biological adaptation to stress cytopenia drug candidate erythroid differentiation exon skipping hematopoietic stem cell differentiation improved inhibitor mortality mouse model mutant novel therapeutic intervention prevent public health relevance stem cell biology stem cell function stem cell genes stem cells therapeutic target

项目摘要

Myelodysplastic Syndrome (MDS) affects at least 10,000 people each year in the U.S., and is particularly prevalent in the aging population. MDS is a clonal disorder arising in hematopoietic stem cells (HSCs), characterized by impaired myeloid and erythroid differentiation and genomic instability. There are currently few therapeutic approaches available to improve cytopenias in MDS patients. Mutations in RNA splicing factors are observed in 50% of MDS cases, and are important contributors to MDS initiation and progression. Most hematopoietic growth factors and cytokines signal through the PI3 kinase (PI3K)/AKT pathway. We have found that compound deletion of the three PI3K isoforms P110a, b, and d in mouse hematopoietic cells leads to a phenotype resembling MDS, with cytopenias, impaired HSC differentiation and genomic instability. Interestingly, we observed enrichment of our TKO HSC expression signature in an MDS patient gene expression dataset. Furthermore, a subset of MDS samples have elevated expression levels of the negative regulator PTEN, suggesting functional inactivation of PI3K in these MDS patients. Our preliminary data reveals that HSCs in PI3K triple knockout (TKO) mice have a defect in autophagy, an intracellular recycling mechanism that is important for the maintenance of HSC differentiation. We found that pharmacologic induction of autophagy can improve differentiation of TKO HSCs. We also observed widespread alterations in mRNA splicing in TKO HSCs. Therefore, PI3K TKO mice are a valuable new model system to study the mechanisms of MDS initiation and progression. We hypothesize that maintenance of PI3K signaling in HSCs is required to maintain HSC differentiation and to protect HSCs from DNA damage. We propose to (1) determine whether induction of autophagy can improve myeloid and erythroid differentiation in MDS patient samples, (2) delineate the mechanism by which PI3K and its downstream kinase AKT control mRNA splicing in HSCs and in MDS, and (3) determine whether MDS cells with splicing factor mutations are more sensitive to inhibition of PI3K/AKT signaling. These approaches will further our understanding of how growth factor and cytokine signaling regulates autophagy and mRNA splicing through PI3K/AKT in MDS initiation. We also plan to test several therapeutic approaches to improve differentiation in MDS, including induction of autophagy and inhibition of PI3K/AKT in MDS with splicing factor mutations.

在美国，骨髓增生异常综合征（MDS）每年至少影响10,000人，在老年人群中尤为普遍。MDS是由造血干细胞（hsc）引起的一种克隆性疾病，其特征是髓系和红系分化受损以及基因组不稳定。目前很少有治疗方法可以改善MDS患者的细胞减少症。RNA剪接因子的突变