Wednesday, June 26, 2024
6/26/2024
During the progression of most chronic kidney diseases (CKD) podocytes are lost, and injury to glomerular endothelial cells, and changes in the composition of the glomerular basement membrane (GBM) lead to alterations of the structure and function of the glomerular filtration barrier. Understanding the mechanisms that induce glomerular cell damage could possibly pave the way to the discovery of new pathways that can be targeted to slow kidney disease progression or possibly reverse it. Data presented in this proposal, using the glomerulus on a chip platform and the FUCCI mouse model that allows tracking of the cell cycle changes in vivo, show that podocytes present an altered binding to their GBM, they exit their quiescent state, and are lost during disease progression in Alport Syndrome (AS) mice, our model of CKD characterized by a defective GBM. We have evidence that miR-193a is upregulated specifically in mouse and human AS podocytes and that its inhibition favors podocyte survival and modulate podocyte interactions with their GBM. Based on our data, we hypothesize that re-establishing glomerular function by modulating important molecular pathways that are responsible for podocyte survival prevents further injury, thus slowing kidney disease progression. Using multiple transgenic AS FUCCI mice and in vitro human systems, we will study the molecular mechanisms that regulate the podocyte cell cycle and their interaction with a defective GBM, typical of AS. Specifically, in Aim 1 we will study in vitro how modulation of miR-193a can “re-program” cellular signaling networks that influence podocyte biology. In Aim 2 we will perform in vivo studies to determine the therapeutic effect of miR-193a inhibitor delivered as cargo of an innovative delivery vehicle based on peptide amphiphile micelle nanoparticles specifically designed to target podocytes in our AS colonies. Successful completion of this proposal will provide novel insights into key factors critical for maintenance of glomerular structure and function. Importantly, this knowledge would likely be applicable to other forms of CKD and possibly facilitate the discovery of new therapeutic agents tailored specifically to sustain podocyte survival and minimize glomerular damage.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
