Carbohydrate-Mediated Platelet Clearance

碳水化合物介导的血小板清除

• 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
• 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

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 正常造血的维持取决于造血茎和 祖细胞（HSPC）。尽管如此，这些程序仍需要通过细胞超支机制进行指导，这些机制正确地传达了 血细胞动态不断变化的需求。我们先前的工作确定了特定于肝细胞的 多聚体内吞受体Ashwell-Morell受体（AMR）与老化的血小板结合，诱导Jak-Stat 血小板蛋白（TPO）的信号传导和产生，造成巨核细胞成熟的细胞因子和 HSPC的分化，血小板产生和维护。除了调节TPO生产和 拆除老化的血小板，我们发现了一种意外的机制，AMR通过该机制调节红细胞生成。 我们的初步数据表明，肝AMR在调节神经蛋白4（NRG4）水平中的作用，该水平是特定的 ERBB4的配体（也称为HER4），这是受体酪氨酸激酶家族的第四个成员 表皮生长因子（EGF）受体（EGFR/HER1），ERBB2/HER2和ERBB3/HER3。全基因组 协会研究（GWAS）表明，NRG4变体与血红蛋白水平的变化有关，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的ERBB4表达和信号传导 干细胞（MSC），导致红细胞生成缺陷，S100A8和S100A9的表达水平升高， 钙结合S100蛋白家族的成员，分别称为加仑蛋白A和B。重组， 细胞外红细胞祖细胞中的S100A8表达水平诱导红细胞 分化缺陷。我们寻求定义NRG4/ERBB4如何影响HSPC稳态和红细胞生成， 包括红细胞岛（AIM 1）。我们将询问NRG4/ERBB4影响MSC的机制 功能，加州素蛋白表达和红细胞生成（AIM 2）。我们使用遗传小鼠的多收益方法 建模，抑制剂，转录组学和生化方法，以允许机械探索 NRG4/ERBB4/calgranulin轴的参与参与促红细胞生成。拟议的调查将 进一步推动治疗性发育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性综合征的患者。