Primary AppointmentCell Biology
Role of Prosecretory Mitogen 'Lacritin' in Epithelial Homeostasis, Secretion and Innate Defense
My lab is interested in epithelial homeostasis, secretion and innate defense. We focus on the human prosecretory mitogen 'lacritin' that we discovered and named out of an unbiased screen for factors regulating ocular tearing (Sanghi et al, J Mol Biol '01). Tears are responsible for homeostasis of the surface of the eye and are essential for innate defense (Karnati et al, Exp Eye Res '13). Both functions are in whole or part contributed by lacritin (Wang et al, J Biol Chem ?13) or by cleavage potentiated fragments of lacritin (McKown et al, J Biol Chem, '14). Truncation and point mutational analysis narrowed the active site in lacritin to an amphipathic alpha helix (Wang et al, J Cell Biol ?06; J Biol Chem ?13), represented by the nineteen amino acid synthetic peptide 'N-94/C-6' - now the subject of a 201 patient, 25 site randomized, placebo controlled phase 2 clinical trial in 'dry eye', the most common eye disease. The trial is sponsored by 'TearSolutions, Inc.' that I cofounded in 2013. Mass spec reveals that N-94/C-6-containing peptides are in plasma and cerebral spinal fluid, implying a potentially very broad hormone-like benefit. New areas of research under exploration include: (i) the lacritin signaling receptor and associated mediators via APEX2 labeling, and via a CRISPR/Cas9 genome-wide screen in collaboration with the Broad Institute, (ii) pro-homeostatic, and sensitivity targeting of IPSC-derived sensory neurons, (iii) lacritin?s cleavage-potentiated bactericidal activity (McKown et al, J Biol Chem '14) represented by the lacritin peptide N-104 (the subject of this application), and (iv) a potential benefit in restoring pancreatic islet function in type 1 diabetes. In 2002, I organized the multi-institutional Lacritin Consortium of collaborating labs (UVa, James Madison University, Eastern Virginia Medical School, Harvard University, University of Illinois at Chicago, Johns Hopkins, UCSF, UC-Berkeley, US Army at Fort Belvoir and others). The Consortium has continuously at least two times a year since to share data and explore new projects.