Role of PGE2 and other eicosanoids in hematopoietic stem cell function

PGE2 和其他类二十烷酸在造血干细胞功能中的作用

• 批准号: 7783278
• 负责人: Louis M Pelus
• 金额: $ 38.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-29 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783278
• 关键词: Adult; Affect; Agonist; Anabolism; Antigen-Presenting Cells; Bone Marrow; CSF3 gene; CXCR4 gene; Cell Count; Cell Cycle; Cell Proliferation; Cell Survival; Cell physiology; Cells; Collection; Complex; Dinoprostone; Eicosanoid Modulation; Eicosanoid Production; Eicosanoids; Endocannabinoids; Engraftment; Exposure to; Family; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hereditary Disease; Homing; In Vitro; Laboratories; Leukotrienes; Light; Lipids; Maintenance; Marrow; Mediating; Methods; Monitor; Myelopoiesis; Outcome; Pathway interactions; Patients; Peripheral Blood Stem Cell; Physiologic pulse; Physiological; Play; Progenitor Cell Engraftment; Property; Prostaglandins; Prostaglandins I; Role; Signal Pathway; Source; Stem cell transplant; Stem cells; Thromboxanes; Translating; Transplantation; Umbilical Cord Blood; Work; hematopoietic stem cell fate; hematopoietic tissue; improved; in vivo; interest; member; peripheral blood; progesterone 11-hemisuccinate-(2-iodohistamine); public health relevance; receptor; self-renewal; stem

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplant is a potentially curative therapy for hematologic and non-hematologic and genetic disorders; however limitations in stem cell number and function can affect engraftment rate and outcomes. In this proposal we will investigate the mechanism of action of eicosanoids in facilitating collection of stem cells and enhancing their engraftment and self-renewal upon transplantation. We believe that the information we derive can be directly translated to improve hematopoietic stem cell transplantation.Eicosanoids are physiological lipids that include prostaglandins, prostacyclins, thromboxanes, leukotrienes, and endocannabinoids. Our early studies demonstrated important negative and positive physiological roles forprostaglandin E2 (PGE2) in normal and abnormal hematopoiesis. Recent evidence suggests that short-term in vitro xposure to PGE2 can enhance the engraftment of hematopoietic stem and progenitor cells (HSPC). In this application, we present new preliminary findings that indicate that PGE2 can increase survival, homing and cell cycle rate of HSPC. In specific aim 1, we will investigate the mechanism of action of PGE2 in enhancing HSPC engraftment and define the receptor subtype and signaling pathways responsible for PGE2-mediated enhancement of HSPC survival, homing and cell cycle and evaluate the role of other eicosanoids on HSC function. Bone marrow is a dynamic tissue and hematopoietic effects of PGE2 are complex and can be positive and negative and direct or amplified or mediated through accessory cells. We have extensively characterized the physiological roles PGE2 can play in cell proliferation and differentiation in vivo, at least at the progenitor cell level. However, given the ability we have today to precisely monitor HSC fate and function, it is critical to define the roles of endogenous and exogenous PGE2 within the host bone marrow in order to determine whether positive or negative modulation of PGE2 synthesis could further facilitate or potentially damage HSC engraftment. In specific aim 2, we will evaluate the roles of endogenous PGE2 and other icosanoids on stem cell function and the hematopoietic microenvironment through the use of selective agonist/antagonist administration and/or selective blockade of PGE2 or alternate eicosanoid production in vivo. G-CSF mobilized peripheral blood stem cells are the primary hematopoietic graft in use for transplant today. Preliminary findings indicate that blockade of PG biosynthesis enhances mobilization by G-CSF and that endocannabinoids, members of the eicosanoid family with activities generally opposite that of the prostaglandins can also mobilize HPC and synergize with G-CSF. In specific aim 3 we will evaluate the utility of eicosanoid pathway modulation for improved hematopoietic mobilization and transplantation and characterize the stem cell roperties of eicosanoid pathway mobilized cells. PUBLIC HEALTH RELEVANCE:Hematopoietic stem cell (HSC) transplantation is a curative therapy; but limitations in HSC number affects engraftment and outcome. Mobilized peripheral blood HSC are widely used, however poor mobilization in patients and normal donors occurs, resulting in inability to collect sufficient HSC. Umbilical cord blood is a relatively untapped source of HSC; however the total number of stem cells that can be obtained is usually too small for adult transplants. In this proposal we will investigate the mechanisms by which eicosanoids enhance HSC function and facilitate engraftment of HSC from all sources , as well as methods to modulate eicosanoid production and activity to obtain more HSC for transplant. If successful, the information we derive will greatly augment the ability to obtain more engraftable HSC and more efficiently deliver them to their marrow niches and can be rapidly and directly translated to improve hematopoietic stem cell transplantation.

描述（由申请人提供）：造血干细胞移植是治疗血液病、非血液病和遗传性疾病的一种潜在治疗方法；然而，干细胞数量和功能的限制会影响植入率和结果。在本提案中，我们将研究类二十烷酸在促进干细胞收集并增强移植后的植入和自我更新方面的作用机制。我们相信，我们获得的信息可以直接转化为改善造血干细胞移植。类二十烷酸是生理脂质，包括前列腺素、前列环素、血栓素、白三烯和内源性大麻素。我们的早期研究表明，前列腺素 E2 (PGE2) 在正常和异常造血过程中具有重要的消极和积极生理作用。最近的证据表明，短期体外暴露于 PGE2 可以增强造血干细胞和祖细胞 (HSPC) 的植入。在 在此应用中，我们提出了新的初步研究结果，表明 PGE2 可以提高 HSPC 的存活率、归巢率和细胞周期率。在具体目标 1 中，我们将研究 PGE2 在增强 HSPC 植入方面的作用机制，定义负责 PGE2 介导的 HSPC 存活、归巢和细胞周期增强的受体亚型和信号通路，并评估其他类二十烷酸对 HSC 功能的作用。骨髓是动态组织，PGE2 的造血作用很复杂，可以是正向的，也可以是负向的，可以是直接的，也可以是通过辅助细胞放大或介导的。我们已经广泛表征了 PGE2 在体内细胞增殖和分化中发挥的生理作用，至少在祖细胞水平上如此。然而，鉴于我们今天有能力精确监测 HSC 的命运和功能，确定内源性和外源性 PGE2 在宿主骨髓中的作用至关重要，以确定 PGE2 合成的正向或负向调节是否会进一步促进或潜在损害 HSC 植入。在具体目标 2 中，我们将通过使用选择性激动剂/拮抗剂给药和/或选择性阻断 PGE2 或体内替代类二十烷酸的产生，评估内源性 PGE2 和其他二十烷酸对干细胞功能和造血微环境的作用。 G-CSF 动员的外周血干细胞是当今用于移植的主要造血移植物。初步研究结果表明，阻断 PG 生物合成可增强 G-CSF 的动员，而内源性大麻素（类二十烷酸家族的成员，其活性通常与前列腺素相反）也可以动员 HPC 并与 G-CSF 产生协同作用。在具体目标 3 中，我们将评估类二十烷酸途径调节对于改善造血动员和移植的效用，并表征类二十烷酸途径动员细胞的干细胞特性。 公共卫生相关性：造血干细胞 (HSC) 移植是一种治疗方法；但 HSC 数量的限制会影响植入和结果。动员外周血HSC被广泛使用，但患者和正常供者的动员效果不佳，导致无法收集足够的HSC。脐带血是一种相对尚未开发的 HSC 来源；然而，对于成人移植来说，可以获得的干细胞总数通常太少。在本提案中，我们将研究类二十烷酸增强 HSC 功能并促进所有来源的 HSC 植入的机制，以及调节类二十烷酸的产生和活性以获得更多用于移植的 HSC 的方法。如果成功，我们获得的信息将大大增强获得更多可移植 HSC 的能力，更有效地将它们输送到骨髓龛，并可以快速、直接转化以改善造血干细胞移植。