Associate Professor

Cell Biology

University of Virginia (Charlottesville, VA)

Director

Biotechnology Training Program

University of Virginia (Charlottesville, VA)

Lacritin in epithelial renewal, secretion and cytoprotection.

My lab is interested in epithelial renewal, viability and secretion. We focus on the human prosecretory mitogen 'lacritin' (Sanghi et al, '01; Ma et al, '07), now known to be conserved in ten other species. As lacritin flows from secretory cells through ducts it may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where stem cell niches are not obvious and duplicating cells are diffusely distributed (Wang et al, '06). Lacritin is also expressed by transit amplifying cells of the cornea. Our exploration of lacritin cell targeting has discovered a novel 'off/on' switch mechanism in which lacritin binding of the ubiquitous cell surface proteoglycan 'syndecan-1' requires prior removal of heparan sulfate chains by 'heparanase' (Ma et al, '06). This restricts lacritin activity to sites of heparanase expression, such as regions of exocrine cell migration, secretion, renewal, and inflammation. Binding is mutually specified by lacritin's C-terminal mitogenic domain and syndecan-1's N-terminus. No binding is seen to syndecans-2 or -4. In contrast other growth factors, such as FGF, Wnt, Hh, TGFbeta, amphiregulin and HGF, bind heparan sulfate chains. This is less selective since heparan sulfate chains are common to all syndecans and most other extracellular proteoglycans. Two lacritin alternative splice forms have been discovered (Ma et al, '07). Both are expected to be inactive based on functional analyses with lacritin deletion mutants. Our exploration of lacritin signaling has sketched out diverging G-alpha/PKCalpha/PLC/calcium/NFAT/COX2 and G-alpha/PKCalpha/PLD/mTOR pathways (Wang et al, '06). This implies upstream involvement of a G-protein coupled receptor to which lacritin can bind perhaps at higher affinity when complexed with syndecan-1. Much remains to be learned about NFAT and mTOR signaling in epithelia, and in particular how lacritin's rapid biphasic signaling is transformed into epithelial mitogenesis, and enhanced viability and secretion. The downstream COX2 signaling is intriguing. COX1/COX2 generation of prostaglandin E2 was recently reported by another group to regulate homeostasis in hematopoietic stem cells. A Lacritin Consortium of collaborating labs within Virginia (in Biomedical Engineering and Ophthalmology at UVa; in Biotechnology at JMU; and in Ocular Pharmacology at EVMS) and outside (Walter Reed Ophthalmology) meets several times a year. One area of joint interest is lacritin's potential as a secretogogue in the treatment of the common eye disease 'dry eye'. This possible utility is preliminarily suggested by preclinical studies.

2007 NIH Director’s Bridge Award

2004 Virginia Biotechnology Educator of the Year Award