Carbohydrate-Mediated Platelet Clearance

碳水化合物介导的血小板清除

基本信息

批准号：
10608645
负责人：
Karin Maria Hoffmeister
金额：
$ 51.7万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608645
关键词：
Acetylgalactosamine Affect Attenuated Binding Biochemical Blood Blood Cells Blood Platelets Bone Marrow Calgranulin A Calgranulin B Carbohydrates Cell Count Cells Communication Data Defect Development Disease Progression Dysmyelopoietic Syndromes ERBB2 gene ERBB3 gene Epidermal Growth Factor Receptor ErbB4 gene Erythroblasts Erythrocytes Erythroid Erythropoiesis Excision Family Galactose Generations Genetic Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Hemoglobin concentration result Hepatic Hepatocyte Homeostasis Human Impairment In Vitro Inflammation Inflammatory Investigation Island Knockout Mice Knowledge Leukocyte L1 Antigen Complex Ligands Liver Macrophage Maintenance Marrow Measures Mediating Megakaryocytes Mesenchymal Stem Cells Modeling Molecular Mus Myelodysplastic/Myeloproliferative Disease Patients Plasma Production Receptor Protein-Tyrosine Kinases Recombinants Red Blood Cell Count Role S100 Calcium Binding Protein S100 Proteins S100A8 gene S100A9 gene Signal Transduction Stromal Cells Testing Thrombopoiesis Thrombopoietin Transcript Up-Regulation Variant Work aged bone marrow mesenchymal stem cell cytokine erythroid differentiation extracellular genetic approach genome wide association study inhibitor insight member mesenchymal stromal cell mouse model neuregulin-4 neutrophil novel therapeutic intervention progenitor programs receptor stem cell function stem cell homeostasis therapeutic development transcriptomics

项目摘要

ABSTRACT Maintenance of normal hematopoiesis depends on developmental programs for the hematopoietic stem and progenitor cell (HSPC). Still, these programs require guidance by cell-extrinsic mechanisms that correctly convey the dynamically changing needs of the blood cells. Our prior work established that the hepatocyte-specific Ashwell-Morell receptor (AMR), a multimeric endocytic receptor, binds to aged platelets, inducing JAK-STAT signaling and production of thrombopoietin (TPO), the cytokine responsible for megakaryocyte maturation and differentiation, platelet production, and maintenance of HSPCs. In addition to regulating TPO production and removing aged platelets, we uncovered an unexpected mechanism by which the AMR regulates erythropoiesis. Our preliminary data suggest a role for the hepatic AMR in regulating Neuregulin 4 (Nrg4) levels, the specific ligand for ErbB4 (also known as HER4), the fourth member of the receptor tyrosine kinase family that includes the epidermal growth factor (EGF) receptor (EGFR/HER1), ErbB2/HER2, and ErbB3/HER3. A genome-wide association study (GWAS) shows that NRG4 variants are associated with changes in hemoglobin levels, and ErbB4 signaling contributes to human and mouse erythropoiesis. Our data shows that an increase in Nrg4 affects ErbB4 expression and signaling in bone marrow mesenchymal stem cells (MSCs), leading to defective erythropoiesis and increased expression levels of S100a8 and S100a9, members of the calcium-binding S100 protein family, known as Calgranulin A and B, respectively. Recombinant, extracellular, and increased S100a8 expression levels in erythrocyte progenitors induce an erythroid differentiation defect. We seek to define how Nrg4/ErbB4 affects HSPC homeostasis and erythropoiesis, including erythroblastic islands (Aim 1). We will interrogate the mechanism by which Nrg4/ErbB4 affect MSC function, calgranulin expression, and erythropoiesis (Aim 2). We use a multipronged approach of genetic mouse modeling, inhibitors, transcriptomics, and biochemical approaches to allow mechanistic exploration into the participation of the Nrg4/ErbB4/calgranulin axis in contributing to erythropoiesis. The proposed investigation will further drive therapeutic development to ameliorate erythropoietic deficiencies in blood disease, including in patients with myeloproliferative neoplasms and myelodysplastic syndrome.

抽象的正常造血功能的维持取决于造血干和造血干的发育程序祖细胞（HSPC）。尽管如此，这些程序仍然需要细胞外在机制的指导，以正确传达血细胞的动态变化的需求。我们之前的工作表明，肝细胞特异性 Ashwell-Morell 受体 (AMR) 是一种多聚体内吞受体，与老化血小板结合，诱导 JAK-STAT 血小板生成素 (TPO) 的信号传导和产生，TPO 是负责巨核细胞成熟的细胞因子 HSPC 的分化、血小板生成和维持。除了规范 TPO 生产和通过去除老化的血小板，我们发现了 AMR 调节红细胞生成的一种意想不到的机制。我们的初步数据表明肝脏 AMR 在调节神经调节蛋白 4 (Nrg4) 水平中发挥作用，具体 ErbB4（也称为 HER4）的配体，受体酪氨酸激酶家族的第四个成员，包括表皮生长因子 (EGF) 受体 (EGFR/HER1)、ErbB2/HER2 和 ErbB3/HER3。全基因组范围关联研究 (GWAS) 显示 NRG4 变异与血红蛋白水平的变化相关，并且 ErbB4 信号传导有助于人类和小鼠红细胞生成。我们的数据表明，Nrg4 的增加会影响骨髓间充质中的 ErbB4 表达和信号传导干细胞（MSC），导致红细胞生成缺陷和 S100a8 和 S100a9 表达水平增加，钙结合 S100 蛋白家族的成员，分别称为钙粒蛋白 A 和 B。重组，细胞外和红细胞祖细胞中 S100a8 表达水平增加诱导红系分化缺陷。我们试图确定 Nrg4/ErbB4 如何影响 HSPC 稳态和红细胞生成，包括红细胞岛（目标 1）。我们将探究Nrg4/ErbB4影响MSC的机制功能、钙颗粒蛋白表达和红细胞生成（目标 2）。我们采用多管齐下的方法来遗传小鼠建模、抑制剂、转录组学和生化方法，以进行机械探索 Nrg4/ErbB4/钙颗粒蛋白轴参与红细胞生成。拟议的调查将进一步推动治疗方法的开发，以改善血液疾病中的红细胞生成缺陷，包括患有骨髓增生性肿瘤和骨髓增生异常综合征的患者。