Recent advance in autoimmunity research reveals that the complement system is able to recognize self targets and initiates inflammatory response in a similar way as with pathogens. This application focuses on one such example of """"""""innate autoimmunity"""""""", renal ischemia reperfusion injury (IRI). The long term goal of this project is to elucidate the pathways by which complement is activated in renal IRI, to determine the complement mediators responsible, define the downstream events of complement activation, and test the therapeutic efficacies of selective complement inhibitors in renal IRI. These studies will use mice globally or tissue-specifically deficient in the membrane complement regulatory proteins DAF, CD59 and Crry.
Our specific aims are: 1) to determine if mice conditionally deficient in Crry (on renal tubules or on endothelial cells) will sustain tubular or glomerular injury either spontaneously or in response to IR challenge. We have developed a Crry gene floxed mouse and will cross this mouse with Aquaporin 2-Cre and Tie-2 Cre transgenic mice to generate tissue-specific Crry gene knockout mice. 2) to determine the pathways by which complement is activated during renal IRI in DAF-/-/CD59-/- mice and characterize the pathogenic natural antibodies and antigens involved. We will cross the DAF-/-/CD59-/- mouse with C4-/-, Ig-/-, C1q-/-, MBL-A-/- &C-/-, fD-/- and properdin-/- mice to achieve this specific aim. 3) to identify the responsible complement mediators and characterize the downstream events leading to renal IRI in DAF-/-/CD59-/- mice. We will use genetic and pharmacologic approaches to evaluate the roles of C3a, C5, C5a, macrophages, neutrophils, eicosanoids and cytokines in renal IRI. 4) to test the therapeutic efficacy of recombinant CR2-Crry and Compstatin, as a local and systemic C3 inhibitor, respectively, in renal IRI. These studies will increase our understanding of the role and mechanism of action of complement in """"""""innate autoimmunity"""""""" and facilitate the development of anti-complement therapies in renal ischemia reperfusion injury, a major cause of acute renal failure in human patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049344-09
Application #
7769525
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2001-09-30
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
9
Fiscal Year
2010
Total Cost
$382,407
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Williams, Allison Lesher; Gullipalli, Damodar; Ueda, Yoshiyasu et al. (2017) C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy. Kidney Int 91:1386-1397
Miao, Jing; Lesher, Allison M; Miwa, Takashi et al. (2014) Tissue-specific deletion of Crry from mouse proximal tubular epithelial cells increases susceptibility to renal ischemia-reperfusion injury. Kidney Int 86:726-37
Lesher, Allison M; Zhou, Lin; Kimura, Yuko et al. (2013) Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis. J Am Soc Nephrol 24:53-65
Lesher, Allison M; Nilsson, Bo; Song, Wen-Chao (2013) Properdin in complement activation and tissue injury. Mol Immunol 56:191-8
Ruseva, Marieta M; Vernon, Katherine A; Lesher, Allison M et al. (2013) Loss of properdin exacerbates C3 glomerulopathy resulting from factor H deficiency. J Am Soc Nephrol 24:43-52
Barata, Lidia; Miwa, Takashi; Sato, Sayaka et al. (2013) Deletion of Crry and DAF on murine platelets stimulates thrombopoiesis and increases factor H-dependent resistance of peripheral platelets to complement attack. J Immunol 190:2886-95
Miwa, Takashi; Sato, Sayaka; Gullipalli, Damodar et al. (2013) Blocking properdin, the alternative pathway, and anaphylatoxin receptors ameliorates renal ischemia-reperfusion injury in decay-accelerating factor and CD59 double-knockout mice. J Immunol 190:3552-9
Song, Wen-Chao (2012) Crosstalk between complement and toll-like receptors. Toxicol Pathol 40:174-82
Dunkelberger, Jason; Zhou, Lin; Miwa, Takashi et al. (2012) C5aR expression in a novel GFP reporter gene knockin mouse: implications for the mechanism of action of C5aR signaling in T cell immunity. J Immunol 188:4032-42
Miwa, Takashi; Zhou, Lin; Maldonado, Michael A et al. (2012) Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice. J Immunol 189:5434-41

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