Role of SMOC2 in Kidney Fibrosis

SMOC2 在肾纤维化中的作用

基本信息

批准号：
9320338
负责人：
Vishal S. Vaidya
金额：
$ 21.3万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-07 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320338
关键词：
Affect Architecture Attention Biological Markers Biopsy Calcium Binding Cause of Death Cell Count Cell Culture Techniques Cell Cycle Arrest Cell Size Cells Cessation of life Chronic Chronic Kidney Failure Cicatrix Collagen Coupled Cyclin D1 Cysteine Cytoskeleton Data Deposition Development Disease Disease Progression Effector Cell Endothelial Cells Epithelial Cells Exhibits Extracellular Matrix Fibroblasts Fibronectins Fibrosis Figs - dietary Focal Adhesion Kinase 1 Folic Acid Functional disorder Genes Genetic Human Injury Integrins Kidney Kidney Diseases Knockout Mice Lead MADH2 gene MAP Kinase Gene MAPK14 gene Medical Medicare Messenger RNA Molecular Mus Myofibroblast Myosin Light Chains Neutrophil Infiltration Organ Outcome Pathogenesis Pathway interactions Patients Play Prevalence Process Proliferating Protein Biosynthesis Proteins Proteomics Public Health RNA Interference Recombinants Resources Role Signal Transduction Signaling Molecule Signaling Protein Smooth Muscle Actin Staining Method Snails Staining method Stains Stimulus Testing Therapeutic Tissues Transforming Growth Factor beta Transgenic Mice Translations Tubular formation United States Up-Regulation Ureteral obstruction Vimentin Work cell type epithelial to mesenchymal transition flexibility in vivo insight integrin-linked kinase interstitial interstitial cell migration mortality mouse model novel overexpression paxillin prevent receptor repaired research study rho scaffold targeted treatment therapeutic target transcriptome sequencing whole genome

项目摘要

Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) such as collagen and fibronectin in and around damaged tissue, which can lead to permanent scarring, organ malfunction and, ultimately, death. Although we have advanced our understanding of the pathogenesis of kidney fibrosis the translation of these findings to humans has been limited and no proven therapeutic strategies can yet detect or prevent the disease progression. We discovered Secreted Protein Acidic and Rich in Cysteines (SPARC) related modular calcium binding 2 (SMOC2) to be amongst the highest upregulated genes in the kidneys of mice subjected to chronic progressive kidney fibrosis. The mRNA and protein levels of SMOC2 were confirmed to be increased (10 to 60-fold) in three mechanistically distinct mouse models of kidney fibrosis as well as in patients with biopsy-proven kidney fibrosis. In the human fibrotic kidney, SMOC2 was concentrated in epithelial cells of the tubular region while also dispersed around the α-Smooth Muscle Actin positive myofibroblasts of the interstitial tissue. In cell culture experiments, recombinant SMOC2 activated fibroblasts to proliferate and migrate - features typical of transitioning into the effector cell of repair – Myofibroblast. SMOC2 treatment of primary human proximal tubular epithelial cells significantly increased vimentin staining (a marker of epithelial cell de-differentiation) along with an increase in cell size − typical of epithelial to mesenchymal transition (EMT); coupled with a decrease in cell number (features of the profibrotic TGFβ pathway). We also found that transgenic mice overexpressing SMOC2 showed significantly enhanced tubulointerstitial fibrosis characterized by substantially higher myofibroblast activation, neutrophil infiltration and collagen accumulation following unilateral ureteral obstruction-induced kidney fibrosis. These results have led us to hypothesize that SMOC2 is a key signaling molecule in the pathological secretome of a damaged kidney that plays a critical role in the reparative scaffold; whose continual presence leads to fibrosis. The objective here is to investigate how induction of SMOC2 in fibroblasts and epithelial cells regulate initiation and progression of kidney fibrosis and whether genetic or pharmacologic modulation of SMOC2 is capable of altering the ultimate outcome from kidney fibrosis. Given that there is no information on the functional significance of SMOC2 upregulation following kidney damage the proposed studies aim at uncovering a novel pathway which may provide opportunities for targeted therapies for patients with kidney fibrosis — an unmet medical need.

纤维化的定义是细胞外基质（ECM）的过度积累，例如胶原蛋白和受损组织内部和周围的纤连蛋白，可能导致永久性疤痕、器官功能障碍，尽管我们对肾纤维化的发病机制有了进一步的了解，但最终还是死亡。这些发现向人类的转化是有限的，目前还没有经过验证的治疗策略可以检测或我们发现富含半胱氨酸的酸性分泌蛋白 (SPARC) 相关的模块化钙结合 2 (SMOC2) 是肾脏中上调最高的基因之一慢性进行性肾纤维化小鼠的 SMOC2 mRNA 和蛋白水平得到证实。在三种机械上不同的肾纤维化小鼠模型以及在活检证实患有肾纤维化的患者在人纤维化肾脏中，SMOC2 集中在上皮细胞中。管状区域的细胞同时也分散在α-平滑肌肌动蛋白阳性肌成纤维细胞周围在细胞培养实验中，重组 SMOC2 激活成纤维细胞增殖和增殖。迁移 - 转变为修复效应细胞的典型特征 - SMOC2 处理肌成纤维细胞。原代人近端肾小管上皮细胞的波形蛋白染色显着增加（上皮细胞的标记物）细胞去分化）以及细胞大小的增加——典型的上皮到间质转化 (EMT)；加上细胞数量的减少（促纤维化 TGFβ 途径的特征）。过表达 SMOC2 的转基因小鼠表现出显着增强的肾小管间质纤维化特征通过显着更高的肌成纤维细胞活化、中性粒细胞浸润和胶原蛋白积累这些结果使我们发现了 SMOC2。是受损肾脏病理分泌组中的关键信号分子，在修复支架；其持续存在会导致纤维化。成纤维细胞和上皮细胞中 SMOC2 的诱导调节肾纤维化的起始和进展 SMOC2 的遗传或药理学调节是否能够改变最终结果鉴于没有关于 SMOC2 上调的功能意义的信息。在肾损伤后，拟议的研究旨在发现一种新的途径，该途径可能提供为肾纤维化患者提供靶向治疗的机会——这是一项未满足的医疗需求。