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Towards Improving Bone Marrow Transplantation via Inhibition of 15-PGDH

通过抑制 15-PGDH 改善骨髓移植

基本信息

批准号：
10319578
负责人：
Amar Desai
金额：
$ 24.9万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-05 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10319578
关键词：
Back Biological Assay Blood Platelets Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Bone Marrow Transplantation CSF3 gene CXCL12 gene Cell Compartmentation Cell Culture Techniques Cells Chemosensitization Clinical Colony-forming units Complication Data Dinoprostone Disease Dose EP4 receptor Engraftment Enzymes Erythrocytes Exposure to Failure Flow Cytometry Generations Genes Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemorrhage Homing Human IL3 Gene Immunohistochemistry In Vitro Individual Knockout Mice Maps Marrow Mediating Mediator of activation protein Methylcellulose Modeling Molecular Mus Natural regeneration PPBP gene PTPRC gene Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Production Prostaglandin E Receptor Prostaglandins Publishing Recovery Research Personnel Role Science Signal Pathway Signal Transduction Speed Stem cell transplant Stromal Cells Testing Time WFDC2 gene Wild Type Mouse Xenograft procedure cell stroma clinical development compare effectiveness curative treatments cytokine daughter cell donor stem cell experience hematopoietic stem cell niche hematopoietic transplantation high risk improved in vivo infection risk inhibitor knock-down knockout gene mouse model neutrophil novel peripheral blood receptor reconstitution response skills small molecule small molecule inhibitor standard of care stem cell population stem cells synergism transcriptome transcriptome sequencing transplant model

项目摘要

Project Summary: Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic malignancies. However, a potentially fatal complication of HST is the high risk of infection and bleeding recipients are exposed to during the up to 4 weeks while awaiting regeneration of peripheral blood neutrophils and platelets. I and collaborators published in 2015 in Science the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH and markedly speeds recovery from HST. As co-first author, I led studies that showed that treating with SW033291 during murine HST enhances transplanted stem cell homing to the bone marrow niche; markedly accelerates recoveries of neutrophils, platelets, and erythrocytes; and increases the effective dose of a bone marrow graft by 5-fold. I showed these effects are mediated by increased bone marrow PGE2, which acts on EP2 and EP4 PGE2 receptors to induce key hematopoietic cytokines, SCF and CXCL12, in bone marrow stromal cells. In this application I now propose elucidate the full cellular and signaling mediators of SW033291's effect on HST and to examine the interaction of SW033291 with G-CSF, the clinical standard of care for stimulating hematopoietic recovery after human HST. I will first comprehensively identify the molecular mediators of SW033291 effect (using RNA-seq) and identify the bone marrow cells in which these mediators are induced and act (e.g. identifying the novel 15-PGDH positive bone marrow cell that is first targeted by SW033291 and then the downstream cells in which SCF and CXCL12 are markedly induced). I will second interrogate the in vivo function of candidate mediators of SW033291 effect, first by testing the ability of this drug to potentiate HST when candidate SW033291 mediators (e.g. 15-PGDH, CXCL12, SCF, plus two new candidate mediators CXCL4 and CXCL7) are genetically deleted from both donor mouse stem cells and recipient mouse bone marrow stroma. I will further map the differential effects of these mediators on hematopoietic stem cells versus bone marrow stromal cells by examining the ability of SW033291 to potentiate HST when candidate mediators are selectively deleted only in donor HSCs or only in recipient bone marrow stromal cells. Using these models I will further dissect each mediator's role at each of three successive stages of SW033291 effect that are: i) potentiating homing of donor HSCs to the recipient marrow; ii) inducing hematopoietic cytokines in the marrow HSC niche; iii) potentiating stem cell generation of daughter cells. Third, I will examine the interaction of SW033291 with G-CSF, the standard of care used to augment neutrophil recovery in human HSC, following up preliminary data that shows an additive to synergistic effect of SW033291 combined with G-CSF, and characterizing the mechanism of this synergy through identification of target changes in the transcriptome and phosphoproteome of selected bone marrow populations from mice treated with these agents singly or in combination. Through these studies I will stepwise acquire the experience and skills that will launch me as new and fully independent investigator.

项目总结：造血干细胞移植(HST)是治疗多种血液病的有效方法。恶性肿瘤。然而，hst的一个潜在的致命并发症是接受者感染和出血的高风险。在等待外周血中性粒细胞和血小板再生的同时，暴露在长达4周的时间内。我和他的合作者在2015年的《科学》杂志上发表了一种名为SW033291的小分子的发现，这种小分子抑制前列腺素降解酶15-前列腺素脱氢酶，显著加快HST的恢复。作为联合优先作者，我领导的研究表明，在小鼠HST期间使用SW033291可以增强移植的干细胞细胞归巢至骨髓壁龛；显著加速中性粒细胞、血小板和红细胞；将骨髓移植的有效剂量增加5倍。我展示了这些影响是由作用于EP2和EP4 PGE2受体的骨髓PGE2增加介导KEY 骨髓基质细胞中的造血细胞因子SCF和CXCL12。在这份申请中，我现在建议阐明SW033291‘S对HST影响的全部细胞和信号调节因子及其相互作用 SW033291联合G-CSF是促进人HST后造血恢复的临床护理标准。我将首先综合鉴定SW033291效应的分子介体(使用RNA-seq)并鉴定这些介体在其中被诱导和作用的骨髓细胞(例如，鉴定新的15-PGDH阳性首先被SW033291靶向的骨髓细胞，然后是SCF和CXCL12所在的下游细胞明显诱导)。我将再次询问SW033291效应的候选介体的体内功能，首先通过测试当候选的SW033291介体(例如15-PGDH， CXCL12、SCF以及两个新的候选介体CXCL4和CXCL7)从两个供体中被基因删除小鼠干细胞和受体小鼠骨髓基质。我将进一步描述这些因素的不同影响通过检测SW033291对造血干细胞和骨髓基质细胞的影响当候选介体仅在供体HSCs或仅在受者骨骼中选择性缺失时，增强HST 骨髓基质细胞。使用这些模型，我将进一步分析每个调解人在三个连续的 SW033291效应的不同阶段：i)促进供者造血干细胞对受者骨髓的归巢；ii)诱导骨髓造血干细胞壁龛中的造血细胞因子；iii)促进子代细胞的干细胞生成。第三, 我将研究SW033291与G-CSF的相互作用，G-CSF是用于增加中性粒细胞的护理标准在人的HSC中恢复，跟踪初步数据显示SW033291的协同作用的添加剂联合G-CSF，并通过识别靶点变化来表征这种协同作用的机制在选定的小鼠骨髓群体的转录组和磷酸蛋白质组中，单独或联合使用特工。通过这些学习，我将逐步获得经验和技能，让我成为新的完全独立的调查员。