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.