To maintain epidermal integrity and homeostasis, proper cell-cell adhesion and communication are critical. For the epidermis to fulfill its primary protective function, the orderly complex process of differentiation, which results in the formation of the outermost stratum corneum must occur. To respond to wounding, the epidermis must undergo proliferation and migration. Several laboratories (listed below) within the dermatology department are investigating the roles of epidermal proteins and glycolipids in these biological processes, and applying them to translational mouse models. The expertise in epidermal cell biology underlies Northwestern's Skin Disease Research Center (SDRC), one of six NIH-funded SDRC's in the US.
Studying the role of the glucocorticoid receptor in carcinogenesis and stem cell maintenance. Involved in development GR-targeted therapies in skin.
The current projects in Dr. Budunova’s lab are centered on the role of the glucocorticoid receptor (GR) as a tumor suppressor gene in skin. We showed that skin-specific GR transgenic animals are resistant to skin carcinogenesis, and GR KO animals are more sensitive to skin tumor development. We are also interested in the role of GR in the maintenance of skin stem cells (SC). We found that GR/glucocorticoids inhibit the expression of numerous SC markers in skin including CD34- a marker of hair follicular epithelial SC, and reduce the proliferative potential of skin SCs.
The glucocorticoids remain among the most effective and frequently used anti-inflammatory drugs in dermatology. Unfortunately, patients chronically treated with topical glucocorticoids, develop side effects including cutaneous atrophy. GR controls gene expression via (i) transactivation that requires GR dimerization and binding as homo-dimer to gene promoters, and (ii) transrepression that is chiefly mediated via negative interaction between GR and other transcription factors including pro-inflammatory factor NF-kB. In general, GR transrepression is the leading mechanism of glucocorticoid anti-inflammatory effects, while many adverse effects of glucocorticoids are driven by GR transactivation.
Our laboratory has been involved in delineation of mechanisms underlying side effects of glucocorticoids in skin. Using GRdim knockin mice characterized by impaired GR dimerization and activation, we found that GR transactivation plays an important role in skin atrophy. These data suggested that non-steroidal selective GR activators (SEGRA) that do not support GR dimerization, could preserve therapeutic potential of classical glucocorticoids but have reduced adverse effects in skin. We are testing effects of the novel SEGRA called Compound A– a synthetic analog of natural aziridine precursor from African bush Salsola Botch in skin. We have also established anti-cancer GR-dependent activity of Compound A in epithelial and lymphoma cells.
Using knockout mice for the major GR target genes including Fkbp5 (GR chaperone) and DDIT4/REDD1 (one of the major negative regulators of mTORC), we discovered that blockage of Fkbp5 and REDD1 significantly changes GR function, and greatly protects skin against glucocorticoid-induced atrophy. This suggests a novel GR-targeted anti-inflammatory therapy where glucocorticoids are combined with inhibitors of GR target genes.
For more information, please see Dr. Budunova’s faculty profile.
See Dr. Budunova's publications in PubMed.
Contact Budunova Lab
Contact the Budunova Lab at 312-503-4669 or visit in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-015, Chicago, IL 60611
Investigating how epithelial cells communicate with one another through adhesion and signaling receptors.
Defects in embryonic development, disruption in normal tissue homeostasis, and unregulated growth in cancer occur when cells no longer sense or respond appropriately to their surroundings. The Getsios laboratory aims to understand how cells receive and interpret information about their environment through adhesion and signaling receptors present on adjacent cell surfaces. Epithelial cells elaborate extensive zones of cell-cell contact that render them particularly well-suited for physically interacting and directly exchanging information with their neighbors. The laboratory uses cell and biochemical approaches in primary epithelial cells isolated from human tissues to study the molecular composition, character and coordination of cell surface proteins that participate in adhesion-signaling networks during normal tissue formation and organization. Genetic reprogramming of primary skin cells is employed to test the importance of novel adhesion-signaling networks during epithelial morphogenesis using a three-dimensional organotypic raft culture model that mimics the human epidermis in vivo.
In the past, we have found that cell adhesion molecules of the cadherin family not only maintain epithelial tissue integrity by stabilizing cell-cell contacts, but also orchestrate intracellular signaling pathways that control epidermal cell differentiation and morphogenesis. Our more recent work is focused on the role of the Eph receptor tyrosine kinase family in regulating epithelial tissue homeostasis. Eph receptors are engaged by membrane-linked ephrin ligands on adjacent cell surfaces and are thus intimately linked to the process of cell-cell adhesion. The activation of Eph receptors can in turn regulate signaling pathways that influence cell adhesion, proliferation, differentiation, and survival.
Our goal is to therapeutically harness these adhesion-signaling networks in order to restore normal epithelial tissue architecture during wound healing, inflammation and cancer.
For more information, please see Dr. Getsios’ faculty profile.
See Dr. Getsios' publications in PubMed.
Contact Getsios Lab
Contact the Getsios Lab at 312-503-5452 or visit us on campus in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-321, Chicago, IL 60611.
Investigating the biology of epithelial stem cells and how stem cells are regulated by microRNAs.
The Lavker laboratory focuses on the biology of epithelial stem cells and the roles of microRNAs (miRNAs) in regulating epithelial homeostasis. In collaboration with Tung-Tien Sun (NYU Medical School), the lab identified and characterized stem cells of the epidermis, hair follicle and corneal epithelium. We have demonstrated that the hair follicle stem cells (located in the bulge region of the follicle) are pluripotent; capable of forming the hair shaft as well as the epidermis. Collectively, these studies have been of major importance for their implications regarding tissue regeneration, hair follicle growth, and carcinogenesis.
Initial investigations on microRNAs (miRNAs) focused on corneal epithelial-preferred miRNAs. Specifically, miR-205 undergoes a unique form of regulation through an interaction with the corneal-preferred miR-184 to maintain SHIP2 levels. SHIP2, a lipid phosphatase, is a target of miR-205, which enhances keratinocyte survival through PI3K-Akt signaling. This miRNA also positively regulates keratinocyte migration by altering F-actin organization and decreasing cell-substrate adhesion.
Recently, the lab has focused on miR-31, which targets factor inhibiting hypoxia-inducible factor-1 (FIH-1). FIH-1 impairs epithelial differentiation via attenuation of Notch signaling. Our results define a previously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part, controlled through a miR-31/FIH-1 nexus. This provides a rationale for development of treatment regimens in patients with diseases affecting abnormal epithelial differentiation (e.g., psoriasis) using inhibitors of FIH-1.
We have also demonstrated that miR-31 targets FIH-1 to positively regulate corneal epithelial glycogen metabolism, which results in the accumulation of glycogen. Increased glucose in the form of glycogen may be a mechanism by which the corneal epithelium is able to withstand periods of hypoxia during eyelid closure or extended contact lens wear. Thus miR-31 may function as a novel means if protecting the corneal epithelium from hypoxic stress.
Most recently, the laboratory has defined the microRNA expression patterns of the stem cell-enriched limbal basal cells and has begun to identify targets that are unique to the limbal epithelium. This should lead to an understanding of how miRNAs regulate epithelial stem cells.
For publication information and more, see the Lab faculty’s profiles:
Contact Lavker Lab
Contact the Lavker Lab at 312-503-2043 or visit us on campus in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-120, Chicago, Illinois, 60611.
Wending Yang, PhD
a) Investigating how epidermal gangliosides regulate signaling at the membrane level.
b) Utilizing siRNA and antisense Spherical Nucleic Acids (SNAs) to treat skin disorders.
The Paller laboratory has two areas of focus. A long-term interest is the role in keratinocytes and other skin cells of lipid raft glycosphingolipids called gangliosides. The laboratory has shown that modulation of ganglioside content genetically (including by SNAs, see below) and biochemically profoundly affects skin cell function through affecting cell signaling. We have found that 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. Regulation of signaling occurs at the membrane level through ganglioside-induced shifts in membrane-based signaling components; for example, ganglioside GM3 (the predominant ganglioside of epithelial cells) directs the formation of a complex that includes the EGFR, caveolin-1, tetraspanin CD82 and PKC-alpha, thereby enabling PKC-alpha to downregulate EGFR signaling. The laboratory has also found that genetic modulation of ganglioside expression in mouse tumor models and human skin leads to the altered characteristics of squamous cell carcinomas. Most recently, our lab has been testing the role of gangliosides in wound healing. Knockout of GM3 synthase, the key enzyme for ganglioside synthesis reverses the wound healing defect in diet-induced obese diabetic mice. GM3 synthase knockout keratinocytes similarly respond to increased glucose paradoxically with accelerated proliferation and migration as a result of improved glucose uptake and activation of growth factor signaling pathways that promote wound healing. We are currently testing the underlying basis for accelerated wound healing in human keratinocytes, as well as introducing gene therapy to accelerate wound healing in diabetic mouse models.
The second area of intense investigation is 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 molsturizer; 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 (Zheng et al, PNAS 2012: 109:11975-80). In addition to delineating the basis for this unprecedented ability to traverse skin and knock down targets, the Paller laboratory is testing siRNA and DNA SNAs as therapeutic agents in mouse and humanized grafted mouse models of psoriasis, epidermolytic ichthyosis, epidermal hyperplastic disorders (such as epidermal nevi and squamous cell carcinomas), melanoma, and diabetic wound healing (see above).
For publication information and more, see Amy Paller's, MD/MS faculty profile.
Contact Paller Lab
Contact the Paller Lab at 312-503-0298 or visit us on campus in the Montgomery Ward Building at 303 E. Chicago Avenue, Ward 9-070, Chicago, Illinois, 60611.
Investigating the mechanisms of adherens junctions assembly, dynamics, and signaling.
The Troyanovsky lab’s research focuses on cadherin, intercellular adhesion, and signaling. Classic cadherins are critical proteins mediating cell-cell adhesion and various signaling pathways responsible for cellular proliferation, differentiation, and morphogenesis. Abnormalities in this system are causal factors in many pathologies, including cancer. The molecular mechanisms of cadherin-based adhesion, however, are largely unknown. How do cadherins establish the adhesion contact? How do they interact with the cytoskeleton? What are the signaling pathways they control? Our laboratory's work is centered around these questions. We are currently working on the following specific projects:
- An individual cadherin molecule’s adhesion site is very weak. To mediate tight adhesion, cadherin molecules form clusters. Recently our lab showed that cadherin clustering is based on two different mechanisms. First, using an extracellular cis-binding site, cadherin sticks laterally in small groups. Additional clustering is promoted by the actin cytoskeleton, binding to which limits cadherin diffusion. The aim of our current study is to understand the regulation of cadherin clustering through modulation of the cadherin – actin filament coupling.
- The formation of cadherin adhesive clusters interconnected to the cytoskeleton is not sufficient to establish functional intercellular junctions. The junctions stimulate formation of actin bundles that is required for epithelial cells to organize their actin cytoskeleton. How adherens junctions initiate actin bundle formation is another direction in our research.
- Cadherin is not the only transmembrane protein in adherens junctions. These structures contain adhesion proteins from the nectin family as well as numerous signaling proteins. We showed that one of such proteins, gamma-secretase, interacts with E-cadherin through p120-catenin. The roles of nectins and gamma-secretase, and the ways they are recruited into adherens junctions are also areas of focus in our lab.
For more information see Sergey Troyanovsky’s, PhD, faculty profile.
View Dr. Troyanovsky's publications at PubMed.
Phone the Troyanovsky Lab at 312-503-9275