Our lab investigates
molecular mechanisms of tissue injury, repair and fibrosis in the kidney
Our Lab is particularly interested in kidney-released growth factors, cytokines and their receptors that control injury, repair and fibrosis in the kidney and that are involved in organ-to-organ cross talk, such as the kidney-lung, kidney-heart or kidney-liver axis; all of which drive significant clinical pathology associated with acute kidney injury/fibrosis. Acute kidney injury (AKI) and fibrotic Chronic kidney disease (CKD) and their secondary complications are highly prevalent world-wide and cause significant morbidity and mortality. Therapeutic strategies to prevent kidney fibrosis and secondary organ damage are lacking.
We have learned much about the structure of growth factors and their receptors, the intracellular pathways they activate and the target genes they address. What is less well understood is the fine regulation in the organism that depends on synthesis, processing and release of growth factors (or receptors) by metalloprotease cleavage (Ectodomain shedding), by exosomes or by secretion in different cell types. In response to growth factor release many other signaling molecules, such as cytokines, are released as secondary signal mediators that integrate the cellular responses to injury and inflammation, in the injured organ (kidney) and in distant organs.
The kidney is a prime example for the participation of epithelial and endothelial cells, as well as fibroblasts and cells of the immune system in factor release. For example, in the kidney, ADAM-mediated release of EGF Ligands induces EGFR activation which is important for tubular repair after injury. However, when EGFR activation is sustained by severe injury, or repeated chronic injury, it leads to fibrosis.
We are defining critical cell types and signaling mediators/pathways involved in tissue injury-repair, fibrosis and organ cross-talk using a combination of cell-based studies, genomic/bioinformatics analysis (shRNA, siRNA, CRISPR-Cas9, functional genomics, single cell RNAseq), novel genetically-engineered mouse models, clinical specimens, and targeted therapeutics. We are using mouse models of acute kidney injury and chronic kidney disease, combined with cardiac, lung or liver injury, as well as cell culture models.
In addition, we study the complex network of intracellular signaling pathways that regulate ectodomain cleavage using biocomputational analysis of a large shRNA dataset of TGFalpha cleavage regulators we generated, and by validating our findings in vitro and in vivo in kidney disease models.