BLR&D Merit Review Research Career Scientist (RCS) Award (IK6)

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The PI is an expert in extracellular matrix (ECM) receptor biology and how these receptors control ECM homeostasis in health and disease. As progressive accumulation of ECM leads to fibrosis, the PI goal is to determine the mechanisms whereby ECM receptors control matrix synthesis/degradation in order to devise more effective anti-fibrotic therapies. Among the matrix receptors the PI focuses on integrins (VA Merit Review) and discoidin domain receptors (DDRs) (NIH/NIDDK R01) in the regulation of collagen synthesis and degradation in kidney injury. The PI’s group has evidence that the collagen receptor integrin α1β1 is a negative regulator of fibrosis and it plays a protective role by: 1) downregulating the activation of the TGF-β receptor in a ligand independent manner and dampening Smad-dependent pro-fibrotic signaling; 2) inhibiting the activation of the EGF receptor; 3) negatively regulating the assembly of the NADPH oxidase thus reducing oxidative stress; and 4) preventing the phosphorylation and nuclear translocation of the ribonucleoprotein Fused in Sarcoma (FUS) (VA Merit Review). In contrast to integrin α1β1, integrin α2β1 and DDR1 are postive regulators of fibrosis and studies from the PI group indicate that genetic deletion of integrin α2β1 or DDR1 protects mice from the development of kidney fibrosis after injury. The PI’s group provides strong evidence that the deleterious action of these two matrix receptors resides in their ability to activate pro-inflammatory (MCP-1) and pro-fibrotic (Stat-3) downstream signaling. In addition, the PI provides the novel finding that DDR1 can regulate collagen production by translocating to the nucleus where it localizes to chromatin to promote the transcription of collagen. Based on these findings, the PI’s goal is to devise peptide-based inhibitors and small molecule inhibitors to target these receptors and/or their downstream signaling. The PI’s group has strong evidence that small-molecule and peptide-based approaches to inhibit integrin α2β1 and FUS nuclear translocation, respectively, have a great promise to be used as anti-fibrotic approaches in vitro and in animal models. Based on these exciting results the PI is currently refining strategies to prevent and ideally halt kidney fibrosis and identifying novel and potentially targetable molecules selectively regulated by integrins and DDRs. The PI studies are published in high rated journals including Journal of American Society of Nephrology, Kidney International, Matrix Biology, Journal of Clinical Investigation, to name a few. In order to be successful, the PI has assembled a team of cell biologists, medicinal chemists, experts in the generation of cell-penetrating peptide- mediated therapeutic molecule, and nephrologists both at the University and VA site. The PI’s area of research is highly relevant to our Veterans because kidney fibrosis and consequent end stage kidney disease are commons in active duty military and Veterans. The work performed by the PI and her team will lead to the development of novel strategies to halt and ideally prevent kidney fibrosis and, hence, improve the quality of lives of our Veterans.