Rudolph Lucas, PhD.
Associate Professor, Vascular Biology Center
Pharmacology and Toxicology
|More about Dr. Lucas|
The main focus of the lab is to identify and characterize novel therapeutic agents that are able to increase alveolar liquid clearance, crucial for proper gas exchange, in conditions of infection and inflammation of the lungs.
Protective Activity of the lectin-like domain of TNF in permeability edema (NHLBI RO1)
The lectin-like domain of TNF, mimicked by the TIP peptide, improves alveolar liquid clearance in multiple animal models of both hydrostatic and permeability edema as well as in a clinical trial in patients with acute lung injury, leading to a clinical interest in its potential use as a treatment for pulmonary edema. Mechanistically, our recently obtained data suggest that the TIP peptide directly activates ENaC upon association with the intracellular carboxy-terminal domain of the alpha subunit. Binding to the alpha subunit stabilizes the channel’s complex formation with MARCKS and PIP2, essential for the open conformation, in the presence of pneumococcal pneumolysin (PLY), the latter of which causes permeability edema through activation of PKC-alpha. Triple knock-in (TKI) mice expressing a TNF mutant lacking a functional lectin-like domain are more prone to develop edema than their wild type counterparts after instillation of a low dose of PLY. The TIP peptide also protects microvascular endothelial cells, which express ENaC, from PLY-induced hyperpermeability, in an amiloride-sensitive manner. Taken together, these data demonstrate a novel mechanism of ENaC activation and suggest a physiological role for the lectin-like domain of TNF in alveolar liquid clearance.
Czikora et al. A Novel TNF-mediated Mechanism of Direct Epithelial Sodium Channel Activation. Am J Respir Crit Care Med. 2014 Jul 16 (+Editorial).
Czikora et al. Protective effect of Growth Hormone-Releasing Hormone agonist in bacterial toxin-induced pulmonary barrier dysfunction. Frontiers in Physiol. 2014. In press.
Lucas R et al. Protein kinase C-α and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability. Am J Respir Cell Mol Biol. 2012; 47(4):445-53 (Cover);
Lucas R et al. Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema. Proc Natl Acad Sci U S A. 2012; 109(6) :2084-9; Dulebo et al. A Computational Study of the Oligosaccharide Binding Sites in the Lectin-Like Domain of Tumor Necrosis Factor and the TNF-derived TIP Peptide. Curr Pharm Des. 2012. 18(27): 4236-43.
Lucas R et al. Cytokine profiling of young overweight and obese female African American adults with prediabetes. Cytokine. 2013 Jun 11. doi:pii: S1043-4666(13)00271-8. 10.1016/j.cyto.2013.05.025.
Lucas et al., Mapping the lectin-like activity of TNF, Science 1994, 263(5148):814-817.
|Information updated as of October 2, 2014|