权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Pcpe2 in Adipose Tissue Remodeling and Lipoprotein Metabolism

Pcpe2 在脂肪组织重塑和脂蛋白代谢中的作用

基本信息

批准号：
10837655
负责人：
Mary G Sorci-Thomas
金额：
$ 19.5万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10837655
关键词：
Address Adipocytes Adipose tissue Award Binding Biological Assay Blood Vessels Body Weight Body Weight decreased Bone Morphogenetic Proteins Brown Fat C-terminal CD36 gene Calories Cardiovascular Diseases Cardiovascular system Cell Differentiation process Cell Respiration Cells Cholesterol Complement DNA Data Diabetes Mellitus Diet Dose Endopeptidases Energy Intake Energy Metabolism Enhancers Extracellular Matrix Proteins Fatty acid glycerol esters Female Funding Gene Expression Genes Genotype Genus Hippocampus Glycoproteins Goals Heart Heart Diseases Hemagglutinin High Fat Diet Histology Howard Temin Award Human Hyperplasia Hypertrophy In Vitro Inflammation Insulin Resistance Knock-out Knockout Mice Link Lipids Lipoproteins Literature Liver Low-Density Lipoproteins Macrophage Mass Spectrum Analysis Measurement Measures Membrane Metabolic Metabolic Diseases Metabolism Mitochondria Mitochondrial DNA Monitor Mucins Mus Names Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Obesity Epidemic Pathway interactions Phenotype Plasma Population Prevalence Procollagen Proliferating Proteins Publications Publishing Recommendation Regulation Regulatory Pathway Reporting Research Risk Rodent Role Seminal Signal Pathway Signal Transduction Stains Stress Structure-Activity Relationship System Testing Text Time Tissue Expansion Tissue Sample Tissues Transforming Growth Factor beta Triglycerides Very low density lipoprotein Visceral Visceral fat Weaning Weight Work adiponectin comparison control cytokine design experience experimental study extracellular feeding gain of function glucose tolerance glycosylation in vivo inhibitor insulin tolerance lipid biosynthesis loss of function male metabolic phenotype mortality mouse model mutant novel novel strategies overexpression precursor cell progenitor recruit response sex single cell sequencing trend uptake

项目摘要

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The increased prevalence of obesity in the US population continues to drive greater risk for developing type 2 diabetes and cardiovascular disease (CVD). Excessive caloric intake stresses adipocytes into storing lipid in an unhealthy manner, directing lipid into existing adipocytes, known as adipocyte hypertrophy. Healthy adipose tissue expansion and remodeling occurs when adipose tissue precursor cells (PC) in the stromal vascular fraction (SVF) differentiate to create new pre-adipocytes which store lipid, called hyperplasia. Single cell sequencing of visceral adipose tissue (VAT) has identified two main types of PCs in the SVF, adipocyte precursor cells (APCs), and fibroinflammatory adipocyte progenitors (FAPs). APC are pre-adipocytes which differentiate into mature adipocytes, while FAPs, secrete cytokines inhibiting APC differentiation. Also influencing APC and FAP lineage are the transforming growth factor beta (TGFb)-like signaling pathways which inhibit adipogenesis, while bone morphogenetic protein (BMP)-like signaling promotes adipogenesis. Little is known about how signaling through these pathways alters the fate of APCs and FAPs especially during increased lipoprotein flux resulting from a high fat diet (HFD). Recently we discovered that both VAT PCs, APCs and FAPs express high levels of the extracellular matrix (ECM) protein, procollagen endopeptidase enhancer protein 2 (Pcpe2, gene name Pcolce2) whose expression decreases as APCs become committed adipocytes. We found that Pcpe2 is significantly upregulated (>2-4-fold by both TGFb1, and/or HFD feeding) suggesting that Pcpe2 may play a role in TGFb-like signaling pathways in VAT PCs. Based on our preliminary data we hypothesize that PC-Pcpe2 expression stimulates TGFb-like and/or suppressing BMP-like signaling pathways in VAT resulting in fibroinflammatory, hypertrophic adipose tissue and thus, unhealthy adipose expansion. To test our hypothesis, we will carry out two aims; Aim 1: Elucidate the mechanism by which Pcpe2’s regulates TGFb and BMP-like signaling using PC-specific Pcpe2-hemagglutinin tagged (HA) over-expressor (ox) (PC-PcpeoxHA) and PC cell-specific Pcpe2 knockout (KO) (PC-Pcpe2KO) mice lines and in Aim 2, investigate Pcpce2’s structure-function relationship based on its newly identified mucin-like O-linked glycoprotein linker domain.

在此处输入文本，这是您的应用程序的新摘要信息。此部分不得超过30行文本。美国人口中肥胖患病率的增加继续推动发展2型糖尿病和心血管疾病（CVD）的风险增加。过量的热量摄入会迫使脂肪细胞以不健康的方式储存脂质，将脂质导入现有的脂肪细胞，称为脂肪细胞肥大。当间质血管部分（SVF）中的脂肪组织前体细胞（PC）分化产生储存脂质的新前脂肪细胞时，发生健康的脂肪组织扩张和重塑，称为增生。内脏脂肪组织（VAT）的单细胞测序已经确定了SVF中的两种主要类型的PC，脂肪细胞前体细胞（APC）和纤维炎性脂肪细胞祖细胞（FAP）。APC是分化为成熟脂肪细胞的前脂肪细胞，而FAP分泌抑制APC分化的细胞因子。同样影响APC和FAP谱系的是抑制脂肪形成的转化生长因子β（TGF β）样信号传导途径，而骨形态发生蛋白（BMP）样信号传导促进脂肪形成。关于通过这些途径的信号传导如何改变APC和FAP的命运，特别是在高脂饮食（HFD）导致的脂蛋白通量增加期间，知之甚少。最近，我们发现VAT PC、APC和FAP都表达高水平的细胞外基质（ECM）蛋白，前胶原内肽酶增强蛋白2（Pcpe 2，基因名称Pcolce 2），其表达随着APC变成定向脂肪细胞而降低。我们发现Pcpe 2显著上调（通过TGF β 1和/或HFD喂养>2-4倍），表明Pcpe 2可能在VAT PC中的TGF β样信号传导途径中起作用。基于我们的初步数据，我们假设PC-Pcpe 2表达刺激VAT中的TGF β样和/或抑制BMP样信号传导途径，导致纤维炎性、肥大的脂肪组织，从而导致不健康的脂肪膨胀。为了验证我们的假设，我们将实现两个目标;目标1：使用PC特异性Pcpe 2-血凝素标记（HA）过表达子（ox）阐明Pcpe 2调节TGF β和BMP样信号传导的机制（PC-PcpeoxHA）和PC细胞特异性Pcpe 2敲除（KO）（PC-Pcpe 2KO）小鼠系，并在目的2中，基于其新鉴定的粘蛋白样O-连接糖蛋白接头结构域研究Pcpce 2的结构-功能关系。