Role of Glycosylation of Dsg1 in Pemphigus acantholysis

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DESCRIPTION (provided by applicant): The P.I. has recently entered the research field of cutaneous autoimmunity bringing a strong molecular biology background. Her career development plan is designed to secure advanced training in autoimmunity, gain research experience in glycosylation study, and enhance technical skills in animal model study. Achievement of these new objectives together with her past expertise will prepare the candidate to develop a research direction, addressing role of glycosylation in cell-adhesion and skin blistering diseases. Under the guidance of Dr. L.A. Diaz, her mentor, she will interact closely with co-mentors/consultants during the proposed research. Her research plan explores the role of glycans on pemphigus antigen/auto antibody interactions. This plan was build upon a very novel finding that two galactose-specific lectins, jacalin and peanut agglutinin (PNA), bind baculovirus expressed pemphigus foliaceus (PF) antigen, desmoglein 1 (rDsgl), and protect mice from PF IgG-induced skin blisters. Other lectins are ineffective. It is hypothesized that binding of jacalin or PNA to Dsg1 interfere the Dsg1/autoantibody interaction by steric hindrance or by inducing conformational changes on Dsgl It is also feasible that pathogenic anti-Dsgl antibodies and lectins compete for the same Dsg1 epitopes. Aim 1 tests the interaction of these lectins with mammalian-expressed Dsg1 (which may be glycosylated differently than the baculovirus-expressed Dsg1). In Aim 2, we will selectively remove the O- or N-glycans of Dsg1 and then test their binding ability to PF IgG and the lectins. In Aim 3, we will map the glycosylation sites on Dsg1 that are bound by lectins and antibodies. In Aim 4, we will test whether lectins bind epidermis in vivo and prevent the binding of pathogenic autoantibodies. We will develop a new strategy to test whether the lectins can prevent progression of existing lesions. The outcome of this grant will shed light on the pathogenesis of PF and may lead to novel therapies. Additionally, the data generated and broad knowledge gained will support the candidate to develop an independent career.