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.
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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
$ 70.66万 - 项目类别:
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
- 资助金额:
$ 70.66万 - 项目类别:
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