Mechanism of Matrix Gla Protein (MGP); Adipose Fibrosis

基质 Gla 蛋白 (MGP) 的作用机制；

基本信息

批准号：
10670995
负责人：
Kristina I Bostrom
金额：
$ 58.54万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-24 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670995
关键词：
Abnormal Endothelial Cell Address Adipose tissue Area BMP4 BMP7 gene Binding Proteins Blood Vessels Bone Morphogenetic Proteins Brown Fat Cell Culture Techniques Cell Separation Cells Chronic Disease Complication Development Diabetes Mellitus Disease Dissection Endothelial Cells Endothelium Excision Extracellular Protein F3 gene Failure Fatty acid glycerol esters Fibrosis Functional disorder GDF10 gene Gene Deletion Gene Expression Profile Gene Mutation Goals Hyperglycemia Hyperlipidemia ICAM1 gene In Vitro Inflammation Inflammatory Knockout Mice Label Ligands Link Location MGP gene Mediating Mediator Mesenchymal Modeling Molecular Mus Mutate Myofibroblast Normal tissue morphology Obesity Pathway interactions Patients Pattern Phenotype Platelet-Derived Growth Factor alpha Receptor Play Population Process Protein Deficiency Proteins Regulation Role Signal Transduction Sorting Source TGF-beta type I receptor Testing Thermogenesis Tissues Transforming Growth Factor beta Vascularization activin receptor-like kinase 1 bone loss bone morphogenetic protein 4 bone morphogenetic protein receptors experimental study extracellular growth differentiation factor 10 inhibitor lipid biosynthesis matrix Gla protein multipotent cell novel therapeutic intervention prevent progenitor protein expression receptor repaired single-cell RNA sequencing stem cells

项目摘要

PROJECT SUMMARY: Adipose fibrosis is characterized by progressive stromal fibrosis that causes adipose dysfunction in obesity, diabetes, and inflammatory conditions. The sustained activation of unwanted myofibroblasts promotes progressive tissue changes with excessive amounts of altered fibrotic matrix. Although PDGFRα+ and CD9+ progenitor cells have been implicated, the cellular mechanisms remain unclear. Matrix Gla Protein (MGP) is an extracellular inhibitor of bone morphogenetic protein (BMP) 4, a mediator of endothelial cell (EC) inflammation. Loss of MGP triggers endothelial-mesenchymal transitions (EndMTs), a source of multipotent cells. We discovered that MGP is expressed in PDGFRα+ and CD9+ progenitor cells, and plays a limiting role in myofibroblast lineage in mice. By characterizing the adipose fibrosis in Mgp-knockout (KO) mice, integrating profiles from single-cell RNA sequencing (scRNA-seq) combined with cell sorting and culture, we propose to dissect the mechanism of MGP in adipose fibrosis. In preliminary studies, global Mgp deletion caused extensive adipose fibrosis in white adipose tissue (WAT) in mice. ScRNA-seq uncovered MGP expression in ECs and progenitors with projected trajectories towards myofibroblasts. Loss of Mgp enhanced abnormal ECs and cell populations with myofibrogenic potential, isolated by FACS. Mice with mutated Mgp lacking BMP- binding displayed fibrosis limited to perivascular areas, suggesting a structural role for MGP. EC-specific Mgp deletion largely mimicked the global fibrotic phenotype. We also found robust changes in brown adipose tissue (BAT) with excessive ECs, myofibroblasts, and abnormal thermogenesis. Potential mechanisms of differentiation involved BMP4/7, the BMP receptor ALK1, the TGFβ receptor ALK5. Our hypothesis is that loss of MGP causes transition and expansion of ECs and specific progenitors, followed by enhanced myofibroblast differentiation, in a two-step model. Aim 1 will elucidate the mechanism by which MGP regulates the transition of ECs and progenitors to myofibroblasts in WAT. We will characterize the Mgp- KO mouse as a new model of adipose fibrosis, using scRNA-seq, FACS and adipogenic cultures. We will assess EC contribution to myofibroblasts by lineage tracing using tdTomato-labeled ECs. In vitro, we will test profibrotic effects of BMP3b and BMP4/ALK1/ALK5 signaling. Aim 2 will determine whether loss of BMP- binding in MGP or endothelial deletion of MGP is sufficient to cause myofibroblasts transitions or a shift in the pattern of fibrosis. Comparisons of myofibroblast transition without BMP binding and endothelial deletion of Mgp allow us to deduce the anti-fibrotic of MGP and the relative importance of endothelial MGP. Aim 3 will characterize BAT after Mgp deletion. We will examine fibrotic and vascular phenotypes in Mgp-KO mice. We will identify MGP-expressing cell populations, their transcriptional profiles and cell trajectories, and determine how MGP helps direct brown adipogenesis by early BMP7. Our results may impact the field of obesity and obesity-related complications and lead to new therapeutic strategies that limit fibrosis in chronic disease.

项目摘要：脂肪纤维化的特征是进行性基质纤维化，导致肥胖症中的脂肪功能障碍，糖尿病和炎症状况。不需要的肌纤维细胞的持续激活促进进行性组织随着纤维化基质的变化而变化。尽管PDGFRα+和CD9+ 祖细胞已暗示，细胞机制仍不清楚。基质GLA蛋白（MGP）是骨形态发生蛋白（BMP）4的细胞外抑制剂，内皮细胞的介体（EC）炎。 MGP触发损失内皮内皮 - 间质转变（EndMTS），多能的来源细胞。我们发现MGP在PDGFRα+和CD9+祖细胞中表达，并且起着极限的作用在小鼠的肌纤维细胞谱系中。通过表征MGP-敲除（KO）小鼠中的脂肪纤维化，整合来自单细胞RNA测序（SCRNA-SEQ）与细胞分类和培养的曲线，我们建议剖析MGP在脂肪纤维化中的机制。在初步研究中，全球MGP缺失引起小鼠白色脂肪组织（WAT）中广泛的脂肪纤维化。 SCRNA-SEQ中发现的MGP表达 EC和祖细胞具有朝着肌纤维细胞的预计轨迹。 MGP的损失增强了异常EC 和具有肌原能的细胞群，由FACS分离。 MGP缺乏BMP-的小鼠结合显示纤维化仅限于周围的纤维化，这表明MGP的结构作用。 EC特异性MGP 缺失在很大程度上模仿了全球纤维化表型。我们还发现棕色脂肪组织的强大变化（BAT）ECS过多，肌纤维细胞和异常热发生。潜在机制分化涉及BMP4/7，BMP受体ALK1，TGFβ受体ALK5。我们的假设是，MGP的丧失会导致EC和特定祖细胞的过渡和扩展通过增强的肌纤维细胞分化，在两步模型中。 AIM 1将阐明该机制 MGP调节WAT中EC和祖细胞向肌纤维细胞的过渡。我们将表征MGP- 使用SCRNA-SEQ，FACS和脂肪生成培养物，KO小鼠是脂肪纤维化的新模型。我们将通过使用TDTomato标记的EC进行谱系跟踪来评估EC对肌纤维细胞的贡献。在体外，我们将测试 BMP3B和BMP4/ALK1/ALK5信号的纤维纤维效应。 AIM 2将确定BMP的损失是否 MGP的MGP或内皮缺失的结合足以引起肌纤维细胞过渡或移动纤维化模式。无BMP结合和内皮缺失的肌纤维细胞过渡的比较 MGP使我们能够推断出MGP的抗纤维化和内皮MGP的相对重要性。目标3意志在MGP删除后表征蝙蝠。我们将检查MGP-KO小鼠中的纤维化和血管表型。我们将识别表达MGP的细胞群体，其转录轮廓和细胞轨迹，并确定 MGP如何通过早期BMP7来指导棕色的脂肪形成。我们的结果可能会影响肥胖领域和与肥胖有关的并发症，并导致新的治疗策略，这些策略限制了慢性疾病的纤维化。

项目成果

期刊论文数量（63）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Serine Protease Activation Essential for Endothelial-Mesenchymal Transition in Vascular Calcification.

DOI：
10.1161/circresaha.115.306751
发表时间：
2015-10-09
期刊：
Circulation research
影响因子：
20.1
作者：
Yao J;Guihard PJ;Blazquez-Medela AM;Guo Y;Moon JH;Jumabay M;Boström KI;Yao Y
通讯作者：
Yao Y

Activation of vascular bone morphogenetic protein signaling in diabetes mellitus.

DOI：
10.1161/circresaha.110.236596
发表时间：
2011-02-18
期刊：
Circulation research
影响因子：
20.1
作者：
Boström KI;Jumabay M;Matveyenko A;Nicholas SB;Yao Y
通讯作者：
Yao Y

Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.

DOI：
10.1161/circresaha.110.219071
发表时间：
2010-08-20
期刊：
Circulation research
影响因子：
20.1
作者：
Yao Y;Bennett BJ;Wang X;Rosenfeld ME;Giachelli C;Lusis AJ;Boström KI
通讯作者：
Boström KI

Cell Transitions Contribute to Glucocorticoid-Induced Bone Loss.

DOI：
10.3390/cells12141810
发表时间：
2023-07-08
期刊：
CELLS
影响因子：
6
作者：
Qiao, Xiaojing;Wu, Xiuju;Zhao, Yan;Yang, Yang;Zhang, Li;Cai, Xinjiang;Ma, Jocelyn A. A.;Ji, Jaden;Lyons, Karen;Bostrom, Kristina I. I.;Yao, Yucheng
通讯作者：
Yao, Yucheng

ABCC6 localizes to the mitochondria-associated membrane.

DOI：
10.1161/circresaha.112.276667
发表时间：
2012-08-17
期刊：
Circulation research
影响因子：
20.1
作者：
Martin LJ;Lau E;Singh H;Vergnes L;Tarling EJ;Mehrabian M;Mungrue I;Xiao S;Shih D;Castellani L;Ping P;Reue K;Stefani E;Drake TA;Bostrom K;Lusis AJ
通讯作者：
Lusis AJ