Integrated signaling of eicosanoids in HSC formation and regeneration

类二十烷酸在 HSC 形成和再生中的整合​​信号传导

• 批准号: 8525395
• 负责人: TRISTA E. NORTH
• 金额: $ 8.4万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-07 至 2014-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525395
• 关键词: Address; Adult; Affect; Agonist; Aorta; Area; Attention; Biological Assay; Biology; Birth; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Cannabinoids; Cell Count; Cell Line; Cell Lineage; Cell physiology; Chemicals; Childhood; Clinical; Data; Defect; Development; Dinoprostone; Disease; Dorsal; Eicosanoid Production; Eicosanoids; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Exposure to; Fertilization; Foundations; Genes; Genetic; Genetic Epistasis; Goals; Gonadal structure; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Homing; Hour; Human; Immune system; Individual; Inflammation Mediators; Inherited; Injury; Lead; Ligands; Mammals; Marrow; Mediating; Mesonephric structure; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Organ; Outcome; Pancytopenia; Primates; Publishing; RUNX1 gene; Recovery; Regulation; Reporter; Research; Role; Screening Result; Signal Transduction; Site; Stem Cell Development; Stem cell transplant; Stem cells; Therapeutic; Time; Transfusion; Transgenic Organisms; Transplantation; Umbilical Cord Blood; United States; Vertebrates; Work; Xenograft procedure; Zebrafish; cannabinoid receptor; cell growth; cellular targeting; chemical genetics; chemotherapy; combinatorial; in vivo; insight; knock-down; leukemia; migration; mortality; novel; programs; repaired; self-renewal; stem cell fate specification; therapeutic target; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Disorders of the hematopoietic system are a common cause of morbidity and mortality in the United States. In vertebrates, definitive hematopoietic stem cells (HSCs) produce each of the mature blood cell lineages of an individual throughout its lifetime. Defects in HSC formation or differentiation can lead to devastating diseases in childhood or to leukemia. The first HSCs arise in the embryo from an area encompassing the dorsal aorta, termed the aorta-gonad mesonephros (AGM) region. Most genes involved in HSC formation are highly conserved across vertebrates, and continue to regulate HSC self-renewal and differentiation in the adult. The transcription factor Runx1, a frequent target of chromosomal mutation in human leukemia, is absolutely required for HSC specification in mammals; runx1 expression is conserved in zebrafish, appearing robustly by 36 hours post fertilization (hpf) in the AGM. Through a zebrafish chemical screen for modifiers of runx1 expression, we have found that compounds related to eicosanoid production and signaling modulate HSC number. The eicosanoid prostaglandin E2 (PGE2) can regulate embryonic HSC formation and adult homeostasis across vertebrate species. In contrast, the function of related eicosanoids, cannabinoids (CB), in HSC development and PGE2-mediated repair has not been addressed. Our long-term goal is to understand the molecular and cellular mechanisms by which various factors interact to affect hematopoiesis. Our objective here is to characterize the functional implications of eicosanoid cross-regulation on HSC formation, proliferation and migration during development and recovery after injury, in both zebrafish and mice. Our central hypothesis is that two related eicosanoid subclasses, PGE2 and CBs, act individually and in concert to exert specific effects on HSCs during embryogenesis and regeneration. This hypothesis has been derived from our own screening results and subsequent preliminary data as well as previously published studies. The rationale for our work is that a detailed understanding of the impact of CB ligands on PGE2-mediated HSC growth and proliferation will enable targeted therapeutic approaches for the treatment of bone marrow failure states, recovery from chemotherapy, or after HSC transplant. In Specfic Aim 1, we plan to investigate the effects of CB agonists/antagonists on HSC specification and proliferation during hematopoietic development in zebrafish. We will examine the conservation of this activity during and after marrow injury. In Specific Aim 2, we plan to analyze the combined effects of CB agonists and PGE2 on HSCs. We postulate that PGE2 and CB-agonists together can increase HSC number in the AGM to a higher level than each of these compounds alone. We will then examine if the interaction between eicosanoids is relevant in directing enhanced marrow recovery after injury in zebrafish and murine transplantation models and in assays with human cord blood. These results are expected to reveal deeper insight into interactive roles of inflammatory mediators in marrow regeneration and have relevance for combinatorial targeting to direct clinical outcome in transfusion biology.

描述（由申请人提供）：造血系统疾病是美国发病率和死亡率的常见原因。在脊椎动物中，永久性造血干细胞（HSC）在其一生中产生个体的每种成熟血细胞谱系。HSC形成或分化的缺陷可导致儿童期毁灭性疾病或白血病。第一批HSC在胚胎中从包围背主动脉的区域产生，称为性腺中肾（AGM）区域。大多数参与HSC形成的基因在脊椎动物中高度保守，并继续调节成体HSC的自我更新和分化。转录因子Runx 1是人类白血病中染色体突变的常见靶点，是哺乳动物HSC特异性的绝对必要条件; Runx 1在斑马鱼中的表达是保守的，在AGM中受精后36小时（hpf）出现。通过对斑马鱼进行runx 1表达修饰剂的化学筛选，我们发现与类花生酸产生和信号传导相关的化合物调节HSC数量。类二十烷酸前列腺素E2（PGE 2）可以调节胚胎HSC的形成和脊椎动物物种的成体体内平衡。相比之下，相关的类花生酸，大麻素（CB），在HSC的发展和PGE 2介导的修复功能尚未解决。我们的长期目标是了解各种因素相互作用影响造血的分子和细胞机制。我们的目标是在斑马鱼和小鼠中，在损伤后的发育和恢复过程中，描述类花生酸交叉调节对HSC形成、增殖和迁移的功能影响。我们的中心假设是，两个相关的类花生酸亚类，前列腺素E2和CB，单独和一致行动，发挥特定的作用，在胚胎发生和再生过程中的HSC。这一假设来自我们自己的筛选结果和随后的初步数据以及先前发表的研究。我们工作的基本原理是，详细了解CB配体对PGE 2介导的HSC生长和增殖的影响，将使有针对性的治疗方法用于治疗骨髓衰竭状态，从化疗中恢复，或HSC移植后。在具体目标1中，我们计划研究CB激动剂/拮抗剂对斑马鱼造血发育过程中HSC特化和增殖的影响。我们将研究这种活性在骨髓损伤期间和之后的保存。在具体目标2中，我们计划分析CB激动剂和PGE 2对HSC的联合作用。我们推测，PGE 2和CB-激动剂一起可以增加AGM中的HSC数量到比这些化合物单独使用更高的水平。然后，我们将研究类花生酸之间的相互作用是否与指导斑马鱼和小鼠移植模型损伤后增强骨髓恢复以及人类脐带血检测相关。这些结果有望揭示炎症介质在骨髓再生中的相互作用，并与输血生物学中直接临床结果的组合靶向相关。