Obesity-induced mesenchymal stem cell senescence

肥胖引起的间充质干细胞衰老

基本信息

  • 批准号:
    10312008
  • 负责人:
  • 金额:
    $ 64.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-12-27 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT/SUMMARY The prevalence of obesity is rising to epidemic proportions. Obesity often leads to endocrine and metabolic derangements, and reduction in its complications could diminish morbidity and mortality, and produce large cost savings. Currently, bariatric surgery is considered the most effective treatment for sustainable weight loss. Obesity triggers cellular damage in multiple organs, partly via induction of premature senescence. This cellular program is characterized by a permanent cell-cycle arrest and altered cellular function, which prompts cells to acquire a senescence-associated secretory phenotype (SASP), a distinctive secretome that involves secretion of inflammatory cytokines and chemokines. Aberrant accumulation of senescent cells exhibiting the SASP phenotype exerts noxious effects on neighboring cells, and drives tissue injury and the aging phenotype. Mesenchymal stem cells (MSC), a ubiquitous cellular repair mechanism, may be injured by ambient risk factors. In obesity adipose tissue-derived MSC might develop cellular senescence (CS) and acquire a SASP phenotype, suggesting that obesity may impede endogenous cellular repair capacity. However, the effects of obesity on CS in human MSC, and the impact of MSC CS on their reparative capacity, remain unknown. Our hypothesis is that obesity evokes senescence in human MSC, which interferes with their capacity to repair injured kidneys. We hypothesize that this impaired MSC function is partly mediated by a phenotype shift in MSC-derived extracellular vesicles (EV) that drive their paracrine effects, but would be reversible upon senolytic pre-treatment of MSC, or following patient weight loss. We will use unique and novel model systems and techniques to pursue specific aims showing that: Specific Aim 1: In human subjects, obesity induces CS in adipose tissue MSC, and interferes with their repair capacity in injured mouse kidneys. Specific Aim 2: The functional impairment in adipose tissue MSC from obese human subjects is partly mediated by a phenotype shift in their membrane-derived EV. Specific Aim 3: MSC-CS and SASP in obese human subjects would be reversible upon bariatric surgery. The proposed studies may uncover novel mechanisms, involving impaired circulating and tissue cellular repair systems, which underlie complications of human obesity. Furthermore, they may establish a novel strategy to blunt this injurious cellular senescence, and thereby boost endogenous kidney repair capability.
抽象/总结

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Efficacy of Human Embryonic Stem Cells Compared to Adipose Tissue-Derived Human Mesenchymal Stem/Stromal Cells for Repair of Murine Post-Stenotic Kidneys.
与脂肪组织来源的人间充质干细胞/基质细胞相比,人胚胎干细胞修复小鼠狭窄后肾脏的功效。
  • DOI:
    10.1007/s12015-022-10443-8
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Siddiqi,Sarosh;Klomjit,Nattawat;Jiang,Kai;Conley,SabenaM;Zhu,Xianyang;Saadiq,IshranM;Ferguson,ChristopherM;Tang,Hui;Lerman,Amir;Lerman,LilachO
  • 通讯作者:
    Lerman,LilachO
Prognostic impact and clinical outcomes of coronary flow reserve and hyperaemic microvascular resistance.
冠状动脉血流储备和充血性微血管阻力的预后影响和临床结果。
Correlation of Intravascular Ultrasound and Instantaneous Wave-Free Ratio in Patients With Intermediate Left Main Coronary Artery Disease.
  • DOI:
    10.1161/circinterventions.120.009830
  • 发表时间:
    2021-06
  • 期刊:
  • 影响因子:
    0
  • 作者:
    El Hajj SC;Toya T;Warisawa T;Nan J;Lewis BR;Cook CM;Rajkumar C;Howard JP;Seligman H;Ahmad Y;Doi S;Nakajima A;Nakayama M;Goto S;Vera-Urquiza R;Sato T;Kikuta Y;Kawase Y;Nishina H;Nakamura S;Matsuo H;Escaned J;Akashi YJ;Davies JE;Lerman A
  • 通讯作者:
    Lerman A
Comparable in vitro Function of Human Liver-Derived and Adipose Tissue-Derived Mesenchymal Stromal Cells: Implications for Cell-Based Therapy.
  • DOI:
    10.3389/fcell.2021.641792
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Yigitbilek F;Conley SM;Tang H;Saadiq IM;Jordan KL;Lerman LO;Taner T
  • 通讯作者:
    Taner T
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Lilach O Lerman其他文献

Endothelium-dependent coronary microvascular dysfunction is associated with advanced coronary plaque characteristics in patients with nonobstructive coronary atherosclerosis
内皮依赖性冠状动脉微血管功能障碍与非阻塞性冠状动脉粥样硬化患者的晚期冠状动脉斑块特征相关
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shigeo Godo;Michel T Corban;Takumi Toya;Rajiv Gulati;Lilach O Lerman;Amir Lerman
  • 通讯作者:
    Amir Lerman
Coronary microvascular endothelial dysfunction is associated with advanced coronary plaque characteristics in patients with early coronary atherosclerosis
冠状动脉微血管内皮功能障碍与早期冠状动脉粥样硬化患者的晚期冠状动脉斑块特征相关
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shigeo Godo;Michel T Corban;Takumi Toya;Rajiv Gulati;Lilach O Lerman;Amir Lerman
  • 通讯作者:
    Amir Lerman
Coronary microvascular endothelial dysfunction is an independent predictor of larger epicardial plaque area and higher plaque burden
冠状动脉微血管内皮功能障碍是较大心外膜斑块面积和较高斑块负荷的独立预测因素
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michel T Corban;Shigeo Godo;Rajiv Gulati;Lilach O Lerman;Amir Lerman
  • 通讯作者:
    Amir Lerman
Coronary microvascular endothelial dysfunction is associated with plaque vulnerability in patients with early coronary atherosclerosis
早期冠状动脉粥样硬化患者冠状动脉微血管内皮功能障碍与斑块易损性相关
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shigeo Godo;Michel T Corban;Rajiv Gulati;Lilach O Lerman;Amir Lerman
  • 通讯作者:
    Amir Lerman
1027-189 Chronic endothelin receptor antagonism preserves endothelial function in a transgenic mouse model of alzheimer's disease
  • DOI:
    10.1016/s0735-1097(04)91902-x
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    Ahmad A Elesber;Piero Bonetti;Joerg Herrmann;Julie Woodrum;Steven Younkin;Lilach O Lerman;Amir Lerman
  • 通讯作者:
    Amir Lerman

Lilach O Lerman的其他文献

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{{ truncateString('Lilach O Lerman', 18)}}的其他基金

Quantitative magnetization transfer MRI for evaluation of renal fibrosis
定量磁化转移 MRI 评估肾纤维化
  • 批准号:
    10337329
  • 财政年份:
    2020
  • 资助金额:
    $ 64.16万
  • 项目类别:
Noninvasive Evaluation of Renal Allograft Fibrosis by MRI
MRI 无创评估同种异体移植肾纤维化
  • 批准号:
    9976272
  • 财政年份:
    2020
  • 资助金额:
    $ 64.16万
  • 项目类别:
Quantitative magnetization transfer MRI for evaluation of renal fibrosis
定量磁化转移 MRI 评估肾纤维化
  • 批准号:
    10549318
  • 财政年份:
    2020
  • 资助金额:
    $ 64.16万
  • 项目类别:
Noninvasive Evaluation of Renal Allograft Fibrosis by MRI
MRI 无创评估同种异体移植肾纤维化
  • 批准号:
    10176331
  • 财政年份:
    2020
  • 资助金额:
    $ 64.16万
  • 项目类别:
Obesity-induced mesenchymal stem cell senescence
肥胖引起的间充质干细胞衰老
  • 批准号:
    10062968
  • 财政年份:
    2018
  • 资助金额:
    $ 64.16万
  • 项目类别:
MSC-derived microvesicles in metabolic syndrome and renovascular disease
间充质干细胞衍生的微泡在代谢综合征和肾血管疾病中的作用
  • 批准号:
    9231450
  • 财政年份:
    2015
  • 资助金额:
    $ 64.16万
  • 项目类别:
Hypoxia and inflammatory injury in human renovascular hypertension
人类肾血管性高血压的缺氧和炎症损伤
  • 批准号:
    8722682
  • 财政年份:
    2014
  • 资助金额:
    $ 64.16万
  • 项目类别:
Noninvasive assessment of renal fibrosis using magnetization transfer MRI
使用磁化转移 MRI 无创评估肾纤维化
  • 批准号:
    9352889
  • 财政年份:
    2014
  • 资助金额:
    $ 64.16万
  • 项目类别:
Low-Energy Shockwave Treatment Distal To Peripheral Vascular Disease
低能量冲击波治疗远端周围血管疾病
  • 批准号:
    8617434
  • 财政年份:
    2014
  • 资助金额:
    $ 64.16万
  • 项目类别:
Hypoxia and inflammatory injury in human renovascular hypertension
人类肾血管性高血压的缺氧和炎症损伤
  • 批准号:
    9049492
  • 财政年份:
    2014
  • 资助金额:
    $ 64.16万
  • 项目类别:

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躯干肌内脂肪组织含量相关因素的检查:性别、年龄和种族差异
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针对年龄相关血管认知障碍的脂肪组织生热作用
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FABP5在脂肪组织年龄相关慢性炎症中的生理作用分析
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