Role of IL-10R signaling in inflammation induced exhaustion of HSC and emergence of JAK2V617F clonal hematopoiesis

IL-10R信号传导在炎症诱导的HSC耗竭和JAK2V617F克隆造血的出现中的作用

• 批准号: 10503059
• 负责人: Angela Goffredo Fleischman
• 金额: $ 22.49万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503059
• 关键词: Acetylcysteine; Affect; Age; Aging; Agonist; Anti-Inflammatory Agents; Antioxidants; Attention; Biological Markers; Blood; Bone Marrow; Bone Marrow Stem Cell; Cell Cycle; Cells; ChIP-seq; Chronic; Clinical Trials; Clonal Hematopoietic Stem Cell; Cytokine Receptors; Cytotoxic Chemotherapy; DNA Methylation; DNA sequencing; Data; Development; Exposure to; Family; Family history of; Family member; Family-Based Registry; Gene Expression; Gene Expression Profiling; Genes; Genetic; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Inflammation; Inflammatory; Interleukin-10; Lead; Ligands; Link; Lipopolysaccharides; Malignant - descriptor; Methylation; Modeling; Mosaicism; Mus; Mutation; Myeloproliferative disease; Oxidative Stress; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Populations at Risk; Predictive Value; Predisposition; Prevalence; Prevention trial; Production; Reactive Oxygen Species; Recombinant Interleukin-10; Recording of previous events; Regulation; Resistance; Role; Screening procedure; Signal Transduction; Stress; TLR4 gene; TNF gene; Testing; Therapeutic; Toll-like receptors; Translating; Transplantation; Wild Type Mouse; Work; aged; aging population; base; biobank; cell type; cytokine; exhaustion; experimental study; fitness; hematopoietic stem cell emergence; hematopoietic stem cell quiescence; member; methylation pattern; monocyte; mutant; negative affect; peripheral blood; preservation; prevent; progenitor; response; stem; stem cell function; stressor; transcriptome sequencing

Revised Project Summary Age and chronic inflammatory stress drive the emergence of mutant bone marrow stem cells that can lead to specific hematologic malignancy associated mutations allow HSC to resist specific stressors could be leveraged toward therapies aimed at neutralizing the selective advantage of the malignant clone. We have recently found that patients with myeloproliferative neoplasm (MPN) have a dampened response to the anti-inflammatory cytokine IL-10 and this leads to persistent production of the inflammatory cytokine TNFα. In a murine Jak2V617F MPN model, pharmacologic blockade of IL-10R signaling enhances the selective advantage of Jak2V617F mutant cells. The objective of this project is to define how JAK2V617F mutant HSC gain a selective advantage over wild-type (WT) HSC when IL-10R is blocked. Our central hypothesis is that dampened IL-10R signaling creates an inflammatory state that negatively affects WT but not JAK2V617F mutant HSC, thus endowing JAK2V617F mutant cells a selective advantage. Moreover, we hypothesize that dampened IL-10R signaling is an intrinsic feature of those predisposed to acquire MPN. In Aim 1 we will determine the prevalence of an IL-10 resistance phenotype among MPN families. We have found that MPN patients display an inability to respond to IL-10, which we term the “IL-10 resistance phenotype”. However, cases with a family history of MPN have not been systematically evaluated for the phenotype, nor have unaffected family members. We will determine the prevalence of the IL-10 resistance phenotype in affected and unaffected members of our growing MPN family registry which currently contains 53 MPN families. In Aim 2 we will identify the genetic basis for blunted IL-10R signaling in MPN. We will perform targeted DNA sequencing and gene expression profiling (i.e., RNA-seq, ChIP-seq, and differential DNA methylation analysis) to identify the underlying mechanism responsible for dampened IL-10 signaling in MPN. Using sorted peripheral blood monocytes we will use Illumina Infinium MethylationEPIC chips to determine if MPN patients and unaffected family members with blunted IL-10 signaling have differential methylation of IL-10R signaling genes. Gene expression profiling will be performed in parallel to determine if the methylation pattern accurately predicts gene expression. We will also perform targeted DNA sequencing, focusing on cytokine receptor pathway genes, and paying close attention to any genes found to have differential methylation and/or expression, to identify the genetic basis for blunted IL-10 signaling in MPN patients.

修订后的项目摘要