权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MOLECULAR MECHANISMS UNDERLYING CLONAL EXPANSION OF HEMATOPOIETIC STEM CELLS

造血干细胞克隆扩增的分子机制

基本信息

批准号：
10469687
负责人：
Yan Liu
金额：
$ 39.38万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469687
关键词：
ATAC-seq Age Aging Biochemical Genetics Biological Assay Blood Bone Marrow Bone Marrow Cells Bone Marrow Transplantation CASP1 gene Cell Death Cell Maintenance Cells Chromatin Clinical Research Clonal Expansion Complex Data Development Disease EZH2 gene Ectopic Expression Elderly Epigenetic Process GADD45G Genes Genetic Genetic Transcription Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic stem cells Histone H3 Hot Spot Human Immunologics Individual Inflammasome Inflammatory Interleukin-1 beta Knowledge Lysine Mediating Modeling Molecular Multiprotein Complexes Mus Mutation Pathway interactions Pharmacology Polycomb Prevention Research Resistance Retroviridae Risk Somatic Mutation TP53 gene Testing Therapeutic Transplantation Tumor Suppressor Genes Tumor Suppressor Proteins Up-Regulation Viral aged aposome base cytokine gene repression genome-wide hematopoietic stem cell expansion hematopoietic stem cell self-renewal in vivo in vivo Model insight leukemia macrophage mouse model mutant novel paracrine progenitor stem stem cell function

项目摘要

PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risks of de novo and therapy-related hematological neoplasms, suggesting that mutations identified in CHIP likely drive disease development. Acquired somatic mutations in tumor suppressor gene TP53 rank in the top five among mutations identified in CHIP. Clinical studies suggest that expansion of hematopoietic stem cells (HSCs) with TP53 mutations predisposes the elderly to hematological neoplasms and other aging-related diseases. However, there is a significant gap in knowledge regarding the mechanisms by which TP53 mutations promote HSC expansion. We recently found that TP53 mutations identified in CHIP enhance HSC self-renewal in mice in vivo. We showed that several mutant p53 proteins found in CHIP, but not wild–type p53, interact with epigenetic regulator EZH2 and enhance its activity. Moreover, we discovered that mutant p53 increases the chromatin accessibility to the NLRP1 inflammasome gene and that NLRP1 expression was upregulated in mutant HSCs, leading to increased secretion of pro-inflammatory cytokine IL-1β. We hypothesize that mutant p53 promotes mutant HSC expansion through two distinct mechanisms. First, mutant p53 interacts with and enhances the activity of epigenetic regulator EZH2 to promote mutant HSC self-renewal. Second, mutant p53 suppresses wild type HSC function through NLRP1 inflammasome-mediated pro-inflammatory pathway. In this proposed research, we will utilize biochemical, genetic, molecular, immunologic, and pharmacological approaches as well as vertebrate models to investigate the cell autonomous and non-autonomous mechanisms by which mutant p53 promotes clonal expansion of HSCs. To test if mutant p53 HSC expansion is mediated through enhanced EZH2 activity and increased H3K27me3, we will determine the impact of genetic and pharmacological inhibition of EZH2 activity on mutant p53 HSC self-renewal in mice. We will then introduce hot-spot TP53 mutations identified in CHIP into human primary HSPCs using retroviruses and examine if mutant p53 increases H3K27me3 levels and promotes HSPC expansion. To elucidate the cell non- autonomous mechanisms of mutant p53-mediated NLRP1 inflammasome activation on HSC expansion, we will determine if mutant p53 HSCs are more resistant to IL-1β exposure than wild-type HSCs. We will also interrogate cytokine secretion in both mouse and human hematopoietic cells using cytokine arrays. Finally, we will perform competitive bone marrow transplantation assays to determine the impact of genetic and pharmacological inhibition of the NLRP1 inflammasome on the clonal expansion of both mouse and human HSCs with TP53 mutations. Our results will provide novel insights into developing new potential target-based therapeutics for prevention and treatment of CHIP and other aging-associated diseases.

项目总结