The broad objective of this renewal is to increase our understanding of the workings of the complement system in causing human disease. The long-term goal is to define inflammatory pathways mediating tissue injury in order to target specific therapeutic agents to prevent or halt the undesirable reaction. Specifically, mutations have been identified in regulatory proteins of the alternative pathway (AP) in atypical hemolytic uremic syndrome (aHUS) and, more recently, in preeclampsia (PE). These risk variants lead to what has been called the """"""""hyperinflammatory complement phenotype"""""""" or the """"""""complement inflammasome"""""""". For a given degree of cellular injury, in these individuals there is excessive activation of the AP resulting in tissue injury and disease states, primarily related to thrombotic lesions in the microvasculature (thrombomicroangiopathy). A large part of this grant is focused on CD46, the complement inhibitory protein that is widely expressed on cell membranes. In the first Specific Aim, we will characterize how CD46 mutations identified in aHUS and PE alter regulatory activity. In part """"""""b"""""""" of this first aim, we will employ the new technology of targeted resequencing of multiple genes implicated in several large cohorts of patients with PE, lupus, antiphospholipid syndrome, and aHUS. Complement and clotting genes will initially receive the most attention.
In Specific Aim II, we will explore the membrane behavior and signaling capabilities of CD46 in multiple cell types including T lymphocytes, epithelial cells and endothelial cells. On many cells, CD46 is down-modulated by ligand engagement and by cross-linking with antibodies. The process by which this is accomplished will be characterized and compared. Proteolytic processing and vesicle formation will be monitored in each cell population to determine their contribution to shedding and signaling. We also have strong evidence for a specific kinase interacting with the cytoplasmic tails of CD46. We will address many unanswered questions about CD46's membrane behavior including shedding, signaling capability, interactions with seven human pathogens and promotion of T regulatory cell development. While CD46's complement inhibitory profile is established, its role in these more recently described phenomena is largely enigmatic.
An overexuberant reaction by the innate immune system to tissue injury and cellular stress is responsible for several diseases involving small blood vessels including life-threatening complications of pregnancy. These individuals carry mutations that give rise to an excessive and undesirable inflammatory reaction leading to blood clots in the microvasculature. Identifying the genetic basis and the inflammatory pathways responsible for these illnesses will allow for targeted therapeutics to prevent and treat the pathologic process.
|Lyzogubov, Valeriy V; Bora, Puran S; Wu, Xiaobo et al. (2016) The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration-Like Phenotype. Am J Pathol 186:2088-104|
|Forneris, Federico; Wu, Jin; Xue, Xiaoguang et al. (2016) Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode. EMBO J 35:1133-49|
|Elvington, Michelle; Liszewski, M Kathryn; Atkinson, John P (2016) Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol Rev 274:9-15|
|Sherbenou, Daniel W; Aftab, Blake T; Su, Yang et al. (2016) Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. J Clin Invest 126:4640-4653|
|Liszewski, M Kathryn; Atkinson, John P (2015) Complement regulator CD46: genetic variants and disease associations. Hum Genomics 9:7|
|Java, Anuja; Liszewski, M Kathryn; Hourcade, Dennis E et al. (2015) Role of complement receptor 1 (CR1; CD35) on epithelial cells: A model for understanding complement-mediated damage in the kidney. Mol Immunol 67:584-95|
|Watson, Rachael; Wearmouth, Emma; McLoughlin, Amy-Claire et al. (2015) Autoantibodies to CD59, CD55, CD46 or CD35 are not associated with atypical haemolytic uraemic syndrome (aHUS). Mol Immunol 63:287-96|
|Schramm, Elizabeth C; Clark, Simon J; Triebwasser, Michael P et al. (2014) Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol Immunol 61:118-25|
|Lyzogubov, Valeriy; Wu, Xiaobo; Jha, Purushottam et al. (2014) Complement regulatory protein CD46 protects against choroidal neovascularization in mice. Am J Pathol 184:2537-48|
|Pinto, Amelia K; Ramos, Hilario J; Wu, Xiaobo et al. (2014) Deficient IFN signaling by myeloid cells leads to MAVS-dependent virus-induced sepsis. PLoS Pathog 10:e1004086|
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