? The purpose of this application is to further define key pathways in kidney fibrosis, particularly the functional relationship between ligands and their receptor in the progression of fibrosis. Our preliminary data supports the hypothesis that the scavenger receptor CD36 mediates the proinflammatory and profibrotic effects of thrombospondin and oxidized lipoproteins during progressive renal fibrosis. In response to chronic injury induced by obstruction, CD36 mediates important fibrogenic responses, as the severity of renal fibrosis is significantly attenuated in CD36 deficient mice and is associated with decreased NF-kappa B activation and oxidative stress despite higher levels thrombospondin and nitrotyrosine, a marker of protein oxidation, in the tubulointerstitium.
The first aim i s to elucidate the profibrotic relationship between CD36 and thrombospondin and oxidized lipoproteins in an animal model of chronic renal fibrosis by: (1) investigating the thrombospondin-CD36 relationship in TGF-beta activation and angiogenesis; and (2) diffentiating oxidant pathways and targets of oxidized protein modification modulated by CD36 through mass spectrometry and 2-D protein gel analysis.
The second aim i s to differentiate macrophage and renal tubular cell dependent effects of CD36 in fibrogenesis using chimeric mouse strategies.
The third aim i s to investigate in vitro mechanisms whereby tubular CD36 modulates intracellular oxidation pathways during fibrosis. By improving our understanding of the key cellular receptors and the pathways they mediate in the progression of renal fibrosis, these studies will help to identify potential therapeutic targets for chronic kidney disease (CKD) with the goal of developing novel therapies to halt or slow the progression of CKD and alleviate the tremendous health burden of end-stage renal disease. This research will prepare the applicant for an academic career as an independent investigator in the field of kidney fibrogenesis. He will obtain further training in molecular biology, biological mass spectrometry analysis, develop in vitro model systems and gain expertise in the field of renal fibrosis. The transition to independence will be facilitated by the rich environment provided under the mentorship of Dr. Allison Eddy and collaborations with Drs. Jay Heinecke and Maria Febbraio, and by joining a large community of productive researchers focusing on the pathobiology of renal disease at the University of Washington. ? ?
|Pennathur, Subramaniam; Pasichnyk, Katie; Bahrami, Nadia M et al. (2015) The macrophage phagocytic receptor CD36 promotes fibrogenic pathways on removal of apoptotic cells during chronic kidney injury. Am J Pathol 185:2232-45|
|Eddy, Allison A; López-Guisa, Jesús M; Okamura, Daryl M et al. (2012) Investigating mechanisms of chronic kidney disease in mouse models. Pediatr Nephrol 27:1233-47|
|López-Guisa, Jesús M; Cai, Xiaohe; Collins, Sarah J et al. (2012) Mannose receptor 2 attenuates renal fibrosis. J Am Soc Nephrol 23:236-51|
|Okamura, Daryl M; Pasichnyk, Katie; Lopez-Guisa, Jesus M et al. (2011) Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis. Am J Physiol Renal Physiol 300:F245-53|
|Okamura, Daryl M; Pennathur, Subramaniam; Pasichnyk, Katie et al. (2009) CD36 regulates oxidative stress and inflammation in hypercholesterolemic CKD. J Am Soc Nephrol 20:495-505|
|Okamura, Daryl M; Lopez-Guisa, Jesus M; Koelsch, Katie et al. (2007) Atherogenic scavenger receptor modulation in the tubulointerstitium in response to chronic renal injury. Am J Physiol Renal Physiol 293:F575-85|