The role of mitochondria in hematopoietic stem cell self-renewal

线粒体在造血干细胞自我更新中的作用

基本信息

批准号：
10116536
负责人：
Marie-Dominique Filippi
金额：
$ 61.51万
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：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116536
关键词：
Address Applications Grants Attenuated Automobile Driving Biological Clocks Blood Blood Cells Bone Marrow Transplantation Cardiolipins Cells Cessation of life Clinical Colony-Forming Units Assay Coupled Crista ampullaris Data Defect Disease Dysmyelopoietic Syndromes Enzymes Event Failure Frequencies Functional disorder Genetic Models Goals Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Homeostasis Human Image Immune Immunofluorescence Immunologic In Vitro Ineffective Hematopoiesis Inner mitochondrial membrane Intervention Knowledge Lead Life Link Lipids Longevity Measurable Mediating Membrane Potentials Mitochondria Modeling Molecular Multipotent Stem Cells Mus Myelogenous Natural regeneration Pathway interactions Pharmacology Phospholipids Physiological Process Production Property Proteins Quality Control Recording of previous events Regenerative capacity Reporter Reporting Research Risk Role Shapes Stress Structural defect Supplementation Testing Tetracyclines Therapeutic Therapeutic Intervention Tissues Transacylase candidate validation daughter cell functional decline functional restoration hematopoietic stem cell self-renewal hematopoietic tissue improved in vivo in vivo evaluation knock-down mitochondrial dysfunction mitochondrial membrane novel novel strategies prevent regeneration potential regenerative self renewing cell self-renewal small hairpin RNA stem cell division stem cell function therapeutic evaluation therapy design tissue regeneration

项目摘要

Abstract Hematopoietic stem cells (HSC) sustain the production of all blood and immune cells throughout life by differentiating into all blood lineages and regenerate long-lived HSC, ie self-renew. However, although HSC have high regenerative potential, the actual capacity of ‘self-renewal’, ie regenerating a daughter cell that has identical properties’ is limited. It is known that HSC progressively lose regenerative potential with divisional history. A clear understanding of the mechanism responsible for HSC functional decline under homeostatic conditions is still lacking. This lack of knowledge has hampered our ability to maintain HSC functions through divisions. The overall goal of this grant application is to understand which physiological mechanisms get triggered in HSCs with replication, which reduce the activity of the HSC pool. We have discovered that once HSCs get activated, mitochondria irreversibly remodel and do not return to homeostatic conditions. HSCs accumulate dysfunctional mitochondria due to a progressive decline in mitochondrial quality control mechanisms, including reduced mitochondrial turnover and dynamism such that HSCs carry mitochondria have that are different in shape and functions. Mechanistically, HSC lose mitochondrial fission activity [ie, loss of the fission regulator Drp1 activity], which causes a decrease in HSC regenerative potential. We hypothesize that HSC mitochondrial remodeling drives HSC functional decline under homeostatic conditions. The main objectives of this proposal are to understand the contribution and mechanisms of how changes in the quality of mitochondria determine HSC functions. Aim1 will further investigate how a change in mitochondrial dynamism and turnover alter HSC functions. We will examine mitochondria remodeling with HSC replication and the impact it has on HSC functions; mechanistically determine which molecular pathways drive mitochondrial defects and HSC attrition; determine the role of mitochondria in human HSC in physiologically relevant models. Aim2 will investigate mechanisms responsible for the loss of mitochondrial quality controls in HSCs with a focus on cardiolipin. We will examine the role of cardiolipin as causal factor of mitochondrial dysfunctions in HSCs. We will test therapeutic potentials for lipid supplementation in ameliorating HSC functions in vivo. The proposed studies provide a unique opportunity to examine the specific contribution of abnormal mitochondrial functions to HSC functional decline with divisions under homeostatic conditions. It will investigate the novel concept that HSCs accumulate dysfunctional mitochondria to drive their functional decline under homeostatic conditions, perhaps as a mean of HSC internal biological clock, which may lead to the identification of novel approaches for pharmacological intervention to maintain HSC functions through divisions.

抽象的造血干细胞 (HSC) 通过以下方式维持整个生命过程中所有血液和免疫细胞的产生：分化成所有血统并再生长寿命的HSC，即自我更新。具有很高的再生潜力，即“自我更新”的实际能力，即再生具有众所周知，HSC 随着分裂而逐渐丧失再生潜力。清楚了解稳态下 HSC 功能下降的机制。这种知识的缺乏阻碍了我们维持 HSC 功能的能力。该拨款申请的总体目标是了解哪些生理机制得到了支持。在 HSC 中触发复制，这会减少 HSC 池的活动。 HSC 被激活，线粒体不可逆地重塑并且不会恢复到稳态状态。由于线粒体质量控制逐渐下降而积累功能失调的线粒体机制，包括减少线粒体周转和活力，使得 HSC 携带线粒体从机制上讲，HSC 失去线粒体裂变活性[即丧失线粒体分裂活性]。裂变调节因子 Drp1 活性]，导致 HSC 再生潜力降低。稳态条件下 HSC 线粒体重塑驱动 HSC 功能下降。该提案的目标是了解质量变化的贡献和机制 Aim1 将进一步研究线粒体活力的变化如何决定 HSC 的功能。我们将研究线粒体重塑与 HSC 复制及其影响。它对 HSC 功能有影响；从机制上确定哪些分子途径会导致线粒体缺陷； HSC 损耗；在生理相关模型中确定线粒体在人类 HSC 中的作用。研究导致 HSC 线粒体质量控制丧失的机制，重点是我们将研究心磷脂作为 HSC 线粒体功能障碍的致病因素的作用。将测试脂质补充在改善体内 HSC 功能方面的治疗潜力。拟议的研究提供了一个独特的机会来检查异常的具体贡献它将研究稳态条件下线粒体功能对 HSC 功能随分裂的影响。造血干细胞积累功能失调的线粒体以驱动其功能衰退的新概念稳态条件，也许作为 HSC 内部生物钟的一种手段，这可能导致识别通过分裂维持 HSC 功能的药物干预新方法。