Targeting the ROS-p38 MAPK Pathway as a Novel Strategy for Stem Cell Expansion

靶向 ROS-p38 MAPK 通路作为干细胞扩增的新策略

• 批准号: 8206643
• 负责人: Gavin Yong Wang
• 金额: $ 18.33万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206643
• 关键词: ATM Gene Mutation; Acute Myelocytic Leukemia; Address; Adult; Affect; Anemia; Apoptosis; Area; Attenuated; Blood; Bone Marrow Transplantation; CD34 gene; Cell Aging; Cells; Clinical; Clinical Trials; Data; Development; Disease; Dysmyelopoietic Syndromes; Engraftment; Flow Cytometry; Future; Goals; Hematopoietic; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Knockout Mice; Lead; MAP Kinase Gene; MAPK14 gene; Mediating; Microscopic; Molecular; Molecular Target; Mus; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Procedures; Proto-Oncogene Protein c-kit; RNA Interference; Reactive Oxygen Species; Regulation; Research; Role; SB 203580; Severe Combined Immunodeficiency; Small Interfering RNA; Sorting - Cell Movement; Source; Staining method; Stains; Stem cells; System; Techniques; Testing; Translating; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Up-Regulation; Validation; clinical application; cytokine; design; exhaustion; gene therapy; human MAPK14 protein; improved; improved functioning; inhibitor/antagonist; innovation; insight; mitogen-activated protein kinase p38; novel; novel strategies; premature; progenitor; self-renewal; stem cell biology

ABSTRACT The use of umbilical cord blood (CB) as a source of hematopoietic stem cells (HSCs) for transplantation therapy is rapidly expanding, particularly for the treatment of acute myeloid leukemia. However, CB-derived HSCs are of limited use in adults because the number of HSCs available in CB is not sufficient; thus, ex vivo expansion of HSCs is needed to bridge this gap in availability. Activation of p38 mitogen-activated protein kinase (p38 MAPK or p38) has been implicated in the pathogenesis of a variety of hematopoietic disorders, including Franconi anemia (FA) and myelodysplastic syndromes (MDS). Furthermore, oxidative stress, mutation of ATM, and loss of FoxO3 all activate p38 MAPK through up-regulation of reactive oxygen species (ROS) and lead to premature exhaustion of HSCs. These studies suggest that activation of the ROS-p38 pathway may negatively affect HSC self-renewal and expansion. Interestingly, inhibition of p38 has been shown to improve the function of HSCs and hematopoietic progenitor cells (HPCs) in FA and MDS patients and to rescue p38 activation-mediated premature exhaustion of HSCs in FoxO3-/- mice. However, the role of the ROS-p38 MAPK pathway in the regulation of human HSC self-renewal and ex vivo expansion is unclear. Our preliminary studies support the hypothesis that targeted inhibition of the ROS-p38 pathway enhances ex vivo expansion of HSCs. The goal of this project is to develop a novel and innovative approach to increase CB HSC ex vivo expansion by targeting the ROS-p38 pathway. Aim 1 will validate the hypothesis that inhibition of the p38 pathway promotes ex vivo expansion of CB HSCs, and Aim 2 will elucidate the mechanisms by which p38 regulates HSC expansion. The results of this study will provide novel insights into the role of the ROS-p38 pathway in the regulation of HSC self-renewal and differentiation. Such information will be essential to the development of innovative culture strategies for the ex vivo expansion of HSCs.

抽象的 使用脐带血（CB）作为造血干细胞（HSC）的来源进行移植疗法 正在迅速扩张，特别是用于治疗急性髓样白血病。但是，CB衍生的HSC是 在成年人中使用有限，因为CB中可用的HSC数量还不够；因此，离体扩展 需要HSC来弥合可用性差距。 p38有丝分裂原激活蛋白激酶的激活（p38 MAPK 或p38）与多种造血疾病的发病机理有关 贫血（FA）和骨髓增生综合征（MDS）。此外，氧化应激，ATM的突变和损失 FOXO3的均通过反应性氧（ROS）的上调激活p38 MAPK，并导致过早 HSC的精疲力尽。这些研究表明，ROS-P38途径的激活可能会对HSC产生负面影响 自我更新和扩展。有趣的是，已经证明对p38的抑制可以改善HSC的功能，并 FA和MDS患者的造血祖细胞（HPC），并挽救P38激活介导的早产 FOXO3 - / - 小鼠中HSC的精疲力尽。但是，ROS-P38 MAPK途径在调节中的作用 人类HSC自我更新和离体扩展尚不清楚。我们的初步研究支持以下假设 靶向抑制ROS-P38途径可增强HSC的体内扩展。这个项目的目标是 开发一种新颖而创新的方法来通过靶向ROS-P38来增加​​CB HSC的体内扩展 路径。 AIM 1将验证抑制p38途径的假设促进CB的离体扩展 HSC和AIM 2将阐明p38调节HSC扩展的机制。这项研究的结果 将提供有关ROS-P38途径在HSC自我更新和 分化。此类信息将对EX的创新文化策略的制定至关重要 HSC的体内扩展。