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Regulation of hematopoietic stem cell self-renewal by GTPase activating protein signaling

GTP酶激活蛋白信号传导调节造血干细胞自我更新

基本信息

批准号：
9096081
负责人：
Marie-Dominique Filippi
金额：
$ 42.03万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096081
关键词：
Activities of Daily Living Affect Applications Grants B-Lymphocytes Biological Assay Blood Blood Cells CD34 gene Cell Respiration Cell Therapy Cell division Cell physiology Cells Clinical Cytokine Signaling Daughter Development Devices Disease Engraftment Equilibrium Failure Functional disorder Future GTPase-Activating Proteins Genetic Goals Health Hematological Disease Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic System Hematopoietic stem cells Human In Vitro Intervention Knock-out Knowledge Lead Life Ligands Link MAPK14 gene Malignant Neoplasms Mediating Mitochondria Modeling Mus Natural regeneration Organelles Oxidative Stress Pancytopenia Pathway interactions Process Production Protocols documentation Regenerative Medicine Regulation Regulatory Element Regulatory Pathway Reporting Role Signal Pathway Signal Transduction Stem cells Stress Testing Therapeutic Tissues Transforming Growth Factor beta Transplantation Work Xenograft procedure autocrine cost design fitness functional outcomes hematopoietic stem cell fate in vivo inhibitor/antagonist innovation insight knock-down leukemia mitochondrial fitness mitochondrial metabolism novel novel therapeutic intervention novel therapeutics overexpression prevent reconstitution regenerative rho rho GTP-Binding Proteins rho GTPase-activating protein self-renewal small molecule inhibitor stem cell biology success

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this grant application is to understand the regulatory pathways that control the regenerative capacity of hematopoietic stem cells (HSCs) during stress hematopoiesis. A clear understanding of how signaling pathways are used to balance HSC self-renewal and differentiation for efficient hematopoietic regeneration is still lacking. It is unclear how signaling pathways control HSC self-renewal in concert with other regulatory elements. This lack of knowledge has hampered our ability to prevent the decline in HSC regenerative capacity associated with stress hematopoiesis and, consequently, has limited the success of HSC-based therapies that require high numbers of HSC. We have recently discovered a novel and clinically important regulatory network of HSC self-renewal, involving crosstalk between Rho GTPase signaling pathways and mitochondria functions that limit HSC regenerative capacity. We reported that genetic deletion of p190-B Rho GTPase Activating Protein (p190-B RhoGAP [p190-B]); a suppressor of Rho GTPase activity, in mice enhanced long-term HSC engraftment and prevented HSC depletion over serial competitive repopulation. P190-B knock-down in human CD34+ cells preserved huCD34+ functions during ex vivo culture. Single cell assays revealed that p190-B loss promoted HSC self-renewal decision over differentiation during divisions; but HSC quiescence and blood lineage development were not affected. Mechanistically, p190-B loss enhanced HSC self-renewal by limiting mitochondrial oxidative stress and subsequent abnormal activation of an autocrine TGFß/p38MAPK stress signaling pathway. We propose that p190-B uses mitochondria to convert oxidative stress into autocrine cytokine signals to instruct HSC fate decision during HSC regeneration. Aim 1 will determine mechanism linking p190-B and Rho signaling to autocrine TGFß1 pathway for HSC self-renewal via. Aim 2 will define how p190-B uses mitochondria and oxidative energy to modulate TGFß - mediated HSC self-renewal. Aim3 will test the effects of pharmacological inhibition of these pathways on human CD34+ fitness in xeno-transplant models. The proposed studies are innovative because it explores the role of major stress pathways in an underexplored fundamental aspect of HSC biology - i.e. a HSC decision to self-renew or to differentiate independent on mature lineage differentiation or HSC quiescence. The work is expected to yield novel insights in mechanism of HSC self-renewal by crosstalk between signaling and mitochondrial metabolism. This study may ultimately lead to the identification of novel targets for pharmacological intervention in regenerative medicine.

描述（由申请人提供）：本资助申请的总体目标是了解在应激造血过程中控制造血干细胞（HSC）再生能力的调控途径。对于信号通路如何用于平衡HSC自我更新和分化以实现有效的造血再生仍然缺乏清楚的理解。目前尚不清楚信号通路如何与其他调控元件一起控制HSC自我更新。这种知识的缺乏阻碍了我们防止与应激造血相关的HSC再生能力下降的能力，因此限制了需要大量HSC的基于HSC的疗法的成功。我们最近发现了一个新的和临床上重要的调控网络的HSC自我更新，涉及之间的串扰Rho GTdR信号通路和线粒体功能，限制HSC的再生能力。我们报道了基因缺失p190-B Rho GT3激活蛋白（p190-B RhoGAP [p190-B]）（一种Rho GT3活性的抑制因子）在小鼠中增强了HSC的长期植入并防止了HSC在连续竞争性再增殖中的耗竭。在人CD 34+细胞中P190-B敲低在离体培养期间保留了huCD 34+功能。单细胞分析表明，p190-B的损失促进HSC自我更新的决定在分裂过程中的分化，但HSC的静止和血液谱系的发展没有受到影响。从机制上讲，p190-B缺失通过限制线粒体氧化应激和随后的自分泌TGF β 1/p38 MAPK应激信号通路的异常激活来增强HSC的自我更新。我们认为p190-B在HSC再生过程中利用线粒体将氧化应激转化为自分泌细胞因子信号，指导HSC的命运决定。目的1探讨p190-B和Rho信号通路与自分泌TGF β 1通路的相互作用机制。目的2将明确p190-B如何利用线粒体和氧化能调节TGF β介导的HSC自我更新。Aim 3将在异种移植模型中检测这些途径的药理学抑制对人CD 34+适应性的影响。拟议的研究是创新的，因为它探讨了主要的压力途径在HSC生物学的一个未充分探索的基本方面的作用-即HSC决定自我更新或分化独立于成熟的谱系分化或HSC静止。该研究有望通过信号转导和线粒体代谢之间的相互作用对HSC自我更新的机制产生新的认识。这项研究可能最终导致识别再生医学中药理学干预的新靶点。