This Mentored Research Scientist Development Award (K01) application describes a career development and research plan designed to position me as an independent investigator in phagocytosis of apoptotic cell (efferocytosis) in kidney injuries. The main research focus is establishing a way to ameliorate acute kidney injury (AKI), a significant clinical problem associated with high morbidity and mortality, which predisposes individuals to chronic renal disease or even death. Our current knowledge suggests that efferocytosis is triggered during AKI and that defects in this process lead to exacerbation of the pathology. However, there is a significant lack of knowledge as to whether boosting efferocytosis results in faster resolution of AKI, and in addition, which cell type(s) should be targeted has not been explored. To this end, we established a novel way to facilitate apoptotic cell clearance by modifying one of the phagocytic receptors to be more active and have applied this to generate a unique mouse model system. I believe this approach will provide proof of principle that enhancing efferocytosis as an approach to enhance rapid resolution and prevention of chronic progressive fibrosis. My preliminary data suggest expression of this phagocytic receptor enhances efferocytosis in primary macrophages and human proximal tubular epithelial cell line. In the current proposal, we will elucidate: 1) the effect of boosting efferocytosis on AKI by using bilateral ischemia reperfusion (IRI) model, 2) identify the cell type(s) in which enhancing apoptotic cell removal affects kidney injuries. The knowledge gained from this project will open up a new research to find a way to target phagocyte to promote efferocytosis for kidney injury therapies. Through this research plan we will 1) use our uniquely created hyper-phagocytic transgenic mouse model for the first time in the field, 2) become proficient with rodent kidney injury models, and 3) develop an understanding of renal physiology with the ultimate goal of establishing and funding an independent laboratory focused on cures and treatments for acute kidney diseases. The career development plan includes training in kidney injury models under the guidance of Dr. Mark D. Okusa at the University of Virginia (UVA) and didactic course work through NIH P50 O'Brien (UAB) to equip me with advanced and comprehensive knowledge of kidney disease models and physiology. For this award, I will be mentored by Dr. Kodi S. Ravichandran, a recognized expert in phagocytosis of apoptotic cells. Additional assistance in planning, troubleshooting, and interpreting results will be provided by Dr. Peter Lobo, Dr. Rahul Sharma and Dr. Victor H. Engelhard for immunology. After successful completion of this training program, an independent NIH funded R01 application will be submitted in the latter part of the K01 award.
The incidence of acute kidney injury (AKI) is increasing worldwide, and is associated with high mortality, morbidity, and risk of chronic kidney disease. As a consequence of gaps in our understanding of the pathophysiology of AKI, adverse effects of pharmacological agents, and a lack of data using good animal models, effective treatment for AKI remains elusive and no approved pharmacological agents exist for the prevention or treatment of AKI. This proposal aims to evaluate the effect of enhancing removal of dying cells on AKI and assess the therapeutic potential of targeting efferocytosis for kidney injuries.
