权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
9521397
负责人：
Louis M Pelus
金额：
$ 39.09万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-29 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9521397
关键词：
Acute Address Affect Agonist Biological Biological Assay Blood Blood Cells Bone Marrow Cell Lineage Cell Proliferation Cell physiology Cells Chronic Chronic stress Clinic Clinical Clinical Trials Collection Complex Diabetes Mellitus Dinoprostone Disease Eicosanoids Engraftment Future Genetic Grant Hematopoiesis Hematopoietic Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Heterogeneity Homeostasis Homing Inflammation Injury Light Malignant Neoplasms Marrow Molecular Molecular Probes Myelogenous Natural regeneration Non-Steroidal Anti-Inflammatory Agents Pathway interactions Peripheral Blood Stem Cell Pharmacologic Substance Pharmacology Physiological Play Police Population Production Property Prostaglandin-Endoperoxide Synthase Prostaglandins Radiation Regulation Role Signal Pathway Signal Transduction Stem cells Stress Stromal Cells Testing Therapeutic Translations Transplantation Umbilical Cord Blood acute stress clinical translation granulocyte hematopoietic cell transplantation improved interest macrophage paracrine peripheral blood progenitor programs public health relevance receptor reconstruction research clinical testing response self renewing cell self-renewal tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Lifelong blood cell production is maintained by hematopoietic stem cells (HSC) that self-renew as well as produce mature blood cells to meet normal physiologic requirements and respond to needs for increased production in response to stress or injury. HSC and lineage restricted progenitor cells (HPC) reside associated with bone marrow microenvirons or niches where non-hematopoietic stromal cells play key roles in determining their retention, fate, trafficking, and function. While hematopoietic microenvironments supporting stem cell function have been known for 40 years, specific populations of cells that contribute to HSC/HPC function have only recently begun to be identified, and controversy exists regarding niche composition and cell contribution. Despite advances, little is still known about cellular or molecular pathways contributing to niche regulation, about regulatory functions within or between niches, and how niche cells differentially regulate HSC functions under homeostasis or in response to stress or disease. We have had a long standing interest in the roles of prostaglandin E2 (PGE2) and the cyclooxygenase (COX) pathway on hematopoiesis and have made numerous conceptual advancements to the understanding of how PGE2 regulates normal and abnormal hematopoiesis. Our recent demonstration that PGE2 affects HSC function through regulation of homing and self-renewal and identification of molecular pathways and agents to fine tuning these effects, has facilitated current clinical testing of PGE2 to enhance HSC transplant. We recently found that blocking PGE2 signaling through the EP4 receptor using non-steroidal anti-inflammatory drugs (NSAIDs) results in differential HPC and HSC trafficking, particularly of HSC with enhanced engraftment potential. This finding is significant in that it highlights the importance of the PGE2 /COX pathway in the niche on HSC/HPC function; identifies the EP4 signaling pathway as a probe to investigate differential trafficking and heterogeneity of niche function; and validates the niche as a pharmacologic target. We believe this regulatory signaling axis is worth further exploration, but more importantly we believe discovery efforts exploring PGE2-EP4 signaling within the niche offer the opportunity to help delineate specific niche components, shed light on a current controversial topic and offers potential new clinical translation opportunities. In this proposal we will utilize the EP4 receptor as a molecular probe t test the hypothesis that PGE2, signaling in one or more cellular niches/niche cells, critically and differentially regulates stromal microenvirons, influencing both the trafficking (retention, egress and function (homing, engraftment) of HSC and HPC at homeostasis and in response to acute and chronic stress. Understanding cellular and paracrine interactions within marrow niches involved in HSC and HPC trafficking and function has major implications for collection of cells for lifesaving hematopoietic transplantation and treatment of various cancers with myeloablative therapies. Since NSAIDs block signaling through all 4 EP receptors, understanding the precise role of EP4 signaling will very likely identify more selective and efficacious therapeutic strategies.

描述（由申请人提供）：终身血细胞生产由造血干细胞（HSC）维持，造血干细胞（HSC）自我更新并产生成熟血细胞，以满足正常生理需求，并响应压力或损伤时增加生产的需求。HSC和谱系限制性祖细胞（HPC）与骨髓微环境或小生境相关，其中非造血基质细胞在决定其保留、命运、运输和功能方面发挥关键作用。虽然支持干细胞功能的造血微环境已经被知道了40年，但有助于HSC/HPC功能的特定细胞群最近才开始被鉴定，并且关于生态位组成和细胞贡献存在争议。尽管取得了一些进展，但对促进小生境调节的细胞或分子途径、小生境内或小生境之间的调节功能以及小生境细胞如何在稳态下或响应于压力或疾病而差异调节HSC功能仍然知之甚少。我们一直对前列腺素E2（PGE 2）和环氧合酶（考克斯）通路在造血中的作用感兴趣，并在理解PGE 2如何调节正常和异常造血方面取得了许多概念性进展。我们最近证明PGE 2通过调节归巢和自我更新以及鉴定分子途径和试剂来微调这些作用而影响HSC功能，这促进了目前PGE 2增强HSC移植的临床测试。我们最近发现，使用非甾体抗炎药（NSAID）通过EP 4受体阻断PGE 2信号传导导致HPC和HSC的差异运输，特别是具有增强植入潜力的HSC。这一发现是重要的，因为它突出了PGE 2/考克斯途径在小生境中对HSC/HPC功能的重要性;鉴定了EP 4信号传导途径作为研究小生境功能的差异运输和异质性的探针;并验证了小生境作为药理学靶标。我们相信这个调节信号轴值得进一步探索，但更重要的是，我们相信探索PGE 2-EP 4信号通路的发现努力提供了帮助描绘特定利基成分的机会，阐明了当前有争议的话题，并提供了潜在的新临床翻译机会。在这个提议中，我们将利用EP 4受体作为分子探针来测试PGE 2在一个或多个细胞小生境/小生境细胞中的信号传导，差异调节基质微环境，影响HSC和HPC在稳态下以及响应急性和慢性应激的运输（保留、外出和功能（归巢、植入）。了解造血干细胞和HPC运输和功能中涉及的骨髓小生境内的细胞和旁分泌相互作用对收集用于挽救生命的造血移植和用清髓性疗法治疗各种癌症的细胞具有重要意义。由于NSAID阻断了所有4种EP受体的信号传导，因此了解EP 4信号传导的确切作用将很可能确定更具选择性和有效的治疗策略。