Role of SMOC2 in Kidney Fibrosis

SMOC2 在肾纤维化中的作用

基本信息

批准号：
9904168
负责人：
Vishal S. Vaidya
金额：
$ 38.26万
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 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904168
关键词：
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 Consumption Cyclins Cysteine Cytoskeleton Data Deposition Development Disease Disease Progression Effector Cell Endothelial Cells Epithelial Cells Exhibits Extracellular Matrix Fibroblasts Fibronectins Fibrosis Focal Adhesion Kinase 1 Folic Acid Functional disorder Genes Genetic Genetic Transcription Human In Vitro Injury Integrins Kidney Kidney Diseases Knockout Mice Lead MADH2 gene MAP Kinase Gene Medical Medicare Messenger RNA Molecular Mus Myofibroblast Myosin Light Chains Organ Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Pharmacology Phenotype Play Prevalence Process Protein Biosynthesis Proteins Public Health RNA Interference Role Signal Transduction Signaling Molecule Signaling Protein Small Interfering RNA Smooth Muscle Actin Staining Method Snails Source Stains Stimulus Stress Fibers Testing Therapeutic Tissues Transgenic Mice Translations Tubular formation United States Up-Regulation cell type epithelial to mesenchymal transition experimental study flexibility gain of function in vivo insight integrin-linked kinase interstitial interstitial cell kidney fibrosis knock-down loss of function migration mortality mouse model new therapeutic target novel overexpression p38 Mitogen Activated Protein Kinase paxillin prevent receptor renal damage rho scaffold targeted treatment therapeutic evaluation 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. We show that SMOC2 is critically involved in kidney fibrosis progression because transgenic mice overexpressing SMOC2 exhibit significantly enhanced tubulointerstial kidney fibrosis whereas SMOC2 knockout mice are protected from kidney fibrosis development. Furthermore, our preliminary data suggests that inhibition of SMOC2 in vitro and in vivo using small interfering RNA (siRNA) protects from kidney fibrosis suggesting a critical pathogenic role of SMOC2 in initiation and progression of the disease. In cell culture experiments we found that SMOC2 activates matrix assembly signaling in the fibroblasts to stimulate stress fiber formation, proliferation and migration – features typical of transitioning into myofibroblasts that are the the effector cells in fibrosis. Whereas, SMOC2 treatment of primary human proximal tubular epithelial cells significantly increases pro fibrotic factors along with an increase in cell size and a decrease in cell number – features consistent with partial epithelial to mesenchymal transition phenotype. 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.

纤维化是由细胞外基质（ECM）（例如胶原蛋白）和纤连蛋白在受损的组织中及其周围，可能导致永久性疤痕，器官故障以及最终，死亡。尽管我们对肾脏纤维化的发病机理有了了解，但这些发现向人类的翻译受到限制，没有可靠的治疗策略可以检测或预防疾病进展。我们发现了分泌的蛋白质酸性并富含半胱氨酸（SPARC）相关的模块化钙结合2（SMOC2）是儿童最高更新的基因之一受到慢性进行性肾纤维化的小鼠。确认了SMOC2的mRNA和蛋白质水平在三种机械上不同的肾纤维化小鼠模型以及在中增加（10至60倍）活检证实的肾纤维化患者。在人类纤维化肾脏中，SMOC2集中在上皮管状区域的细胞，同时也分散在α-平滑肌肌动蛋白阳性肌纤维细胞周围间质组织。我们表明SMOC2与肾纤维化进展至关重要，因为过表达SMOC2暴露的转基因小鼠显着增强了肾小球纹状肾脏纤维化 SMOC2基因敲除小鼠免受肾脏纤维化的发展。此外，我们的初步数据建议使用小干扰RNA（siRNA）在体外和体内抑制SMOC2可保护肾脏纤维化表明SMOC2在疾病的起始和进展中起关键的致病作用。在细胞中培养实验我们发现SMOC2激活成纤维细胞中的基质组装信号传导以刺激压力纤维形成，增殖和迁移 - 过渡到肌纤维细胞的典型特征纤维化中的效应细胞。而SMOC2治疗原代人近端肾小管上皮细胞显着增加了纤维化因子以及细胞大小的增加和细胞数量的减少 - 与部分上皮到间充质转变表型一致的特征。这些结果使我们进入假设SMOC2是受损肾脏的病理分泌组中的关键信号分子，在修复脚手架中起关键作用；其连续存在导致纤维化。这里的目的是研究成纤维细胞和上皮细胞中SMOC2的诱导如何调节主动性和进展肾纤维化以及SMOC2的遗传还是药物调节能够改变最终肾纤维化的结果。鉴于没有有关SMOC2功能意义的信息肾脏损害后的上调拟议的研究旨在发现一种新的途径，这可能为肾纤维化患者提供靶向疗法的机会 - 未满足的医疗需求。