Regulation of Lymphatic and Vascular Remodeling in Acute Kidney Injury - PROJECT SUMMARY: This NIH F30 application describes plan for mentored research and career development for the PI, Gelare Ghajar-Rahimi. The scientific premise of this proposal is focused on the response of the kidney endothelial system to acute kidney injury (AKI), a major complication in up to 20% of hospitalized and 60% of critically ill patients. Despite the high mortality rate and incidence, targeted therapies to treat AKI have not been successfully developed. Homeostasis of lymphatic and blood endothelial cells is vital to maintaining kidney health and influences AKI pathogenesis. In response to injury, kidney lymphatic vessels (LV) undergo a process of expansion termed lymphangiogenesis (LA) that mitigates kidney damage; density of peritubular blood capillaries decreases, contributes to sustained hypoxia and impairs kidney function. Enhancing LA while simultaneously impeding peritubular capillary rarefaction therefore holds immense promise as a therapeutic approach. These two populations have never been studied concurrently in the context of AKI, limiting our ability to develop endothelia-modulating therapies. Here, I aim to elucidate the cellular origins of de novo LA and the mechanisms governing the endothelial remodeling following AKI. My preliminary data and existing literature suggest that 1) de novo LA arises from a progenitor population of pre-existing lymphatic endothelial cells (rather than myeloid- lineage as some older studies posit) and 2) the divergent responses of blood and lymphatic endothelial populations to injury may be explained by the influence of NF-kB signaling within injured proximal tubule cells. My central hypothesis is that that damaged proximal tubules, through NF-kB signaling, promote transcriptional changes in endothelial cells that contribute to lymphatic expansion and vascular rarefaction. I will test this hypothesis through advanced microscopy and single cell transcriptomics and a variety of in vitro and in vivo experiments, including the use of an inducible lymphatic reporter mouse and mice deficient in NF-kB expression in proximal tubules. These findings will significantly advance our understanding of the mechanisms by which kidney endothelial populations respond to injury and could establish NF-kB as a novel therapeutic target in AKI. The proposed training plan for the PI is sponsored by co-mentors Anupam Agarwal, MD, and James George, PhD. Included in the training plan are experiences that will help Gelare develop in three major areas: 1) rigorous lymphatic and kidney research, which includes developing familiarity with the existing literature, critical evaluation of data, and training in the responsible conduct of research; 2) rigorous training in advanced bioinformatics and next-generation sequencing analysis and 3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research, critical molecular biology and advanced bioinformatics skills necessary for the PI’s future career as a physician-scientist focused on cellular and molecular mechanisms of disease.
