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：
10320951
负责人：
Marie-Dominique Filippi
金额：
$ 60.69万
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/10320951
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）在一生中维持所有血液和免疫细胞的产生区分所有血统并再生长寿命的HSC，即自我更新。但是，尽管HSC 具有很高的再生潜力，即“自我更新”的实际能力，即再生一个具有相同的属性是有限的。众所周知，HSC逐渐失去再生潜力历史。对稳态下HSC功能下降的机制的清晰了解条件仍然缺乏。缺乏知识阻碍了我们通过部门。该赠款应用的总体目标是了解哪些物理机制得到在具有复制的HSC中触发，从而减少了HSC池的活性。我们已经发现一次 HSC被激活，线粒体不可逆转地重塑，不要返回稳态条件。 HSC 由于线粒体质量控制的逐渐下降，导致线粒体累积功能失调机制，包括降低的线粒体更新和动态性，使HSC携带线粒体具有形状和功能不同。从机械上讲，HSC失去线粒体裂变活性[即，损失裂变调节剂DRP1活性]，这会导致HSC再生潜力的降低。我们假设这一点 HSC线粒体重塑在稳态条件下驱动HSC功能下降。主该提案的目标是了解质量变化的贡献和机制线粒体确定HSC功能。 AIM1将进一步研究线粒体动力学的变化和周转改变HSC功能。我们将通过HSC复制和影响检查线粒体重塑它具有HSC功能；机械机械地确定哪种分子途径驱动线粒体缺陷和 HSC损耗;确定线粒体在人体HSC中的作用在物理相关模型中。 AIM2将研究负责HSC中线粒体质量控制损失的机制，重点是 Cardiolipin。我们将研究心脂蛋白作为HSC中线粒体功能障碍的因素的作用。我们将测试用于改善体内HSC功能的脂质补充的治疗潜力。拟议的研究提供了一个独特的机会来检查异常的特定贡献线粒体功能可在稳态条件下通过分裂的HSC功能下降。它将调查 HSC会积累功能障碍线粒体的新颖概念，以推动其功能下降稳态条件，也许是HSC内部生物时钟的平均值，这可能导致识别通过分裂维持HSC功能的新型药物干预方法的新方法。