Our Research

A long-term interest of our laboratory is the role of lipid signaling pathways in keratinocytes, including lipid raft glycosphingolipids called gangliosides. The laboratory pioneered studies showing that genetic or biochemical modulation of ganglioside content profoundly affects skin cell function through their impact on cell signaling. For example, increases in membrane ganglioside expression suppress function of the epidermal growth factor receptor, insulin receptor, insulin-like growth factor receptor-1, and integrins, whereas depletion of ganglioside content stimulates receptor activation. The progenitor ganglioside, GM3, accumulates in diabetic skin and ganglioside depletion using genetic and biochemical approaches reverses the cutaneous innervation abnormalities and accelerates diabetic wound healing in human 3D and mouse diet-induced obese diabetic models.

A second area of interest is in immune abnormalities in psoriasis, with an emphasis on the impact of obesity. In both humans and mouse models, obesity increases the severity of psoriasis. We have shown that the pro-inflammatory effect of obesity depends on reduction of adiponectin and that adiponectin mimetics reverse the tending towards psoriasis exacerbation through suppression of PPAR-gamma activation, reduction of Th17 skewing and increases in Treg cell activity.

Finally, our group is known for the topical application of siRNA and antisense spherical nucleic acids (SNAs) as a novel therapy for skin disorders. SNAs, in which the oligomers are densely arrayed around a central gold nanoparticle, were originally developed by the Mirkin laboratory at Northwestern. We have found that SNAs are: a) readily taken up into cultured keratinocytes; b) able to penetrate through the mouse and human epidermal barriers after application in a common moisturizer; c) suppress genes at nM to pM concentrations; d) have minimal off-target or immune effects after application; and e) to date, have shown no systemic or cutaneous toxicity. These studies have moved forward into showing improvement after topical application of SNAs directed against ganglioside GM3 synthase (diabetic wound healing), TNF or IL17RA or, using a bispecific, both targets (for psoriasis), and TGF-beta or CTGF for scars.

Amy Paller, MS, MD, focuses her clinical work on inflammatory skin disorders and rare genetic disorders of skin. Under her leadership, Northwestern University Feinberg School of Medicine hosts centers of excellence for ichthyosis (group of scaling disorders) and epidermolysis bullosa (group of blistering disorders). Through this connection and with the Northwestern Skin Biology and Diseases Resource-based Center, Feinberg has an extensive biobank of cultured skin cells, tissue and tape stripped skin from patients with these genetic disorders. The laboratory has participated in assessment of inflammatory skin diseases in children (especially atopic dermatitsis/eczema and psoriasis) and genetically-altered skin using omics approaches, including transcriptomics, proteomics, lipidomics and microbiome studies.

In concert with this clinical focus, the Paller Laboratory primarily focuses on inflammatory skin diseases and the development of novel therapeutic approaches. The laboratory has studied diabetic wounds for the past decade and is now focused on understanding the role of various subtypes of sensory nerves with cutaneous afferents in healing as well as in a variety of mouse models of inflammatory skin diseases and wound-associated disorders in which cutaneous innervation is altered. As an extension of this work, the Paller laboratory is investigating the underlying molecular basis for itch and pain in skin disease and how sensory nerve subsets may contribute (e.g., the blistering disease epidermolysis bullosa and common inflammatory skin diseases). In collaboration with faculty from Northwestern University’s International Institute for Nanotechnology, we have been targeting specific immune pathways to suppress their excess activation that leads to skin disease. In other collaborative work, we are delivering RNA replicons as a new gene therapy approach using epidermolysis bullosa as a model.

The other new area of focus is investigating the role of ceramides, crucial components of the skin's lipid barrier, in maintaining skin integrity in atopic dermatitis, psoriasis and ichthyosis. These conditions are associated with a known deficiency in the unique ceramides of skin, contributing to the impaired barrier function. Replenishment of deficient ceramides is a focus in therapeutic strategies for these inflammatory skin conditions, emphasizing their importance in restoring and fortifying the skin barrier to alleviate symptoms and enhance overall skin health. We have been the first team to use untargeted lipidomics as a means to explore epidermal barrier lipids, which is an unbiased approach to discovering relative expression of >600 skin ceramides, as well as other barrier lipids, in healthy or diseased skin samples and compare these alterations with clinical, transcriptional and proteomic alterations.