Obesity-induced dysfunction of human MSC in peripheral microvascular repair
肥胖引起的人间充质干细胞在外周微血管修复中的功能障碍
基本信息
- 批准号:10516515
- 负责人:
- 金额:$ 70.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdipose tissueAgeAttenuatedBiological ModelsBobcatBody Weight decreasedBone MarrowCardiovascular DiseasesCell physiologyCellsChronicClinicalCost SavingsCytosineDiabetes MellitusDown-RegulationEndocrineEndothelial CellsEnhancersEnzyme Inhibitor DrugsEpidemicEpigenetic ProcessEventExhibitsFamily suidaeFatty acid glycerol estersFunctional disorderGene ExpressionGene TargetingGenesHarvestHistonesHumanImpairmentIn VitroInflammationInjuryKidneyKidney DiseasesLife Style ModificationLinkMagnetic Resonance ImagingMediatingMesenchymalMetabolicMethodsMethylationMicroRNAsMitochondriaMitochondrial DNAModificationMusObesityOrganPathogenesisPatientsPeptide antibodiesPeptidesPeripheralPeripheral Vascular DiseasesPeripheral arterial diseasePlasmaPredispositionPrevalenceProcessPropertyQuality of lifeRegulationRenal Artery StenosisRoleSamplingSecondary toStromal CellsStructureSystemTechniquesTestingTherapeuticThinnessTissuesVascular Diseasesangiogenesisbariatric surgerybasecardiovascular risk factorcell injurycitrate carriercritical limb Ischemiaeffective therapyfallsfunctional disabilityhuman subjectimprovedin vivoin vivo imaginginjuredinjury recoverymicroCTmitochondrial dysfunctionmortality riskmouse modelneutralizing antibodynovelobese patientsparacrinepromoterprotective effectprotein expressionrepair functionrepairedreparative capacityrestorationstemtissue repairtooltranscriptome sequencing
项目摘要
Abstract
Obesity triggers cellular damage and impedes tissue recovery from injury, and its escalating prevalence
may promote complications of peripheral vascular disease, such as critical limb ischemia (CLI) or renal artery
stenosis (RAS). Reducing complications of obesity could diminish the risk of death, improve quality of life, and
produce extensive cost savings. This application is based on the scientific premise that obesity increases
tissue susceptibility to injury by interfering with normal defense and repair processes associated with
mesenchymal stem/stromal cells (MSCs). MSCs constitute an effective endogenous cellular repair system,
but obesity may blunt their efficacy. We found that obesity-induced MSC dysfunction in pigs was associated
with altered mitochondrial structure and function, but the mechanisms of mitochondrial damage in human MSC
and its contribution to regulation of MSC function in human obesity remain unknown.
Our central hypothesis is that human obesity engages epigenetic mechanisms that impair human MSC
mitochondrial structure and function and render MSC functionally deficient. We speculate that obesity
alters in MSC the epigenetic states of micro-RNA (miR) miR-181a, a key miR that targets mitochondrial DNA
and negatively regulates their function. A consequent fall in levels of the mitochondrial derived peptide (MDP)
MOTS-c in turn impairs function and tissue repair capacity of MSC in obesity. To test our hypothesis, we will
define gene expression and epigenetic states of mitochondrial targeting miRNAs and MOTS-c in human
adipose tissue-derived MSC and elucidate their functional significance for both MSCs and their mitochondria.
Our Specific Aims will pursue 3 hypotheses. Aim 1: Human obesity induces MSC miR-181a expression and
in turn mitochondrial and MSC structural damage and dysfunction. Using RNA-seq we will identify miR-181a as
a key miR upregulated in MSCs from patients with obesity vs. healthy controls. Its role in regulating MSC and
mitochondrial function and structure will be assessed in vitro and in vivo (in mice with CLI or RAS) using novel
in vivo imaging and ex vivo techniques. Aim 2: Human obesity engages epigenetic mechanisms to alter miR-
181a. We will define the epigenetic landscape of miR-181a using MeDIP-seq, and its contribution to MSC
repair in vitro and in vivo using an epigenetic modifier. Aim 3: A fall in MOTS-c owing to mitochondrial damage
contributes to functional impairment of ‘obese MSC’. Using novel MDP-seq we will pinpoint MOTS-c as a
unique MDP linking mitochondrial to cellular integrity in MSC. MSC treated with MOTS-c peptide or neutralizing
antibody will be characterized, and restoration of ‘obese’ MSC function tested both in vitro and in vivo.
The proposed studies, employing cutting edge techniques, may uncover novel mechanisms underlying cell
damage and impaired repair in human obesity. These studies will advance understanding of the pathogenesis
of cellular damage, and likely contribute towards management of patients with obesity and vascular disease.
抽象的
肥胖会引发细胞损伤并阻碍组织从损伤中恢复,其患病率不断上升
可能会促进周围血管疾病的并发症,例如严重肢体缺血(CLI)或肾动脉
狭窄(RAS)。减少肥胖并发症可以降低死亡风险,提高生活质量,
产生大量成本节约。该应用程序基于肥胖增加的科学前提
通过干扰与相关的正常防御和修复过程,组织对损伤的敏感性
间充质干细胞/基质细胞(MSC)。 MSCs构成有效的内源性细胞修复系统,
但肥胖可能会削弱它们的功效。我们发现肥胖引起的猪 MSC 功能障碍与
线粒体结构和功能发生改变,但人类 MSC 中线粒体损伤的机制
其对人类肥胖中间充质干细胞功能调节的贡献仍不清楚。
我们的中心假设是人类肥胖涉及损害人类 MSC 的表观遗传机制
线粒体结构和功能并导致 MSC 功能缺陷。我们推测肥胖
改变 MSC 中微小 RNA (miR) miR-181a 的表观遗传状态,miR-181a 是靶向线粒体 DNA 的关键 miR
并对其功能进行负面调节。线粒体衍生肽 (MDP) 水平随之下降
MOTS-c 反过来又损害肥胖中 MSC 的功能和组织修复能力。为了检验我们的假设,我们将
定义人类线粒体靶向 miRNA 和 MOTS-c 的基因表达和表观遗传状态
脂肪组织来源的 MSC 并阐明它们对 MSC 及其线粒体的功能意义。
我们的具体目标将追求 3 个假设。目标 1:人类肥胖诱导 MSC miR-181a 表达并
进而导致线粒体和间充质干细胞结构损伤和功能障碍。使用 RNA-seq,我们将 miR-181a 鉴定为
与健康对照相比,肥胖患者的 MSC 中一个关键的 miR 上调。其在调节 MSC 和
线粒体功能和结构将使用新颖的方法在体外和体内(在患有 CLI 或 RAS 的小鼠中)进行评估
体内成像和离体技术。目标 2:人类肥胖利用表观遗传机制来改变 miR-
181a.我们将使用 MeDIP-seq 定义 miR-181a 的表观遗传景观,及其对 MSC 的贡献
使用表观遗传修饰剂进行体外和体内修复。目标 3:线粒体损伤导致 MOTS-c 下降
导致“肥胖间充质干细胞”的功能障碍。使用新颖的 MDP-seq,我们将确定 MOTS-c 作为
独特的 MDP 将 MSC 中的线粒体与细胞完整性联系起来。用 MOTS-c 肽或中和处理的 MSC
抗体将被表征,并在体外和体内测试“肥胖”MSC功能的恢复。
拟议的研究采用尖端技术,可能会揭示细胞的新机制
人类肥胖造成的损伤和修复受损。这些研究将增进对发病机制的了解
细胞损伤,并可能有助于肥胖和血管疾病患者的治疗。
项目成果
期刊论文数量(0)
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Alfonso Eirin其他文献
Alfonso Eirin的其他文献
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{{ truncateString('Alfonso Eirin', 18)}}的其他基金
Role of mitochondrial microRNAs (mitomiRs) in endogenous renal repair
线粒体 microRNA (mitomiRs) 在内源性肾修复中的作用
- 批准号:
10583380 - 财政年份:2023
- 资助金额:
$ 70.66万 - 项目类别:
Obesity-induced dysfunction of human MSC in peripheral microvascular repair
肥胖引起的人间充质干细胞在外周微血管修复中的功能障碍
- 批准号:
10653231 - 财政年份:2022
- 资助金额:
$ 70.66万 - 项目类别:
Role of mitochondrial microRNAs (mitomiRs) in endogenous renal repair
线粒体 microRNA (mitomiRs) 在内源性肾修复中的作用
- 批准号:
10471652 - 财政年份:2021
- 资助金额:
$ 70.66万 - 项目类别:
Mitochondrial injury interferes with endogenous renal repair in experimental renovascular disease
线粒体损伤干扰实验性肾血管疾病的内源性肾修复
- 批准号:
9805789 - 财政年份:2019
- 资助金额:
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A potential role for mitoprotection in preserving the kidney in metabolic syndrome and renal artery stenosis
有丝分裂保护在代谢综合征和肾动脉狭窄中保护肾脏的潜在作用
- 批准号:
9115146 - 财政年份:2015
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$ 70.66万 - 项目类别:
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