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Northwestern University Feinberg School of Medicine
Department of Dermatology
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Genetic & Epigenetic Modulation

Manipulating the expression in genes in primary keratinocytes is a key component of research and a challenge in translational research. In joint research with Northwestern's nanotechnology experts, department members have been investigating new strategies to deliver of siRNA, antisense DNA and miRNA into primary keratinocytes, as well as through the stratum corneum and into mouse and human epidermis to treat inflammatory, neoplastic and genetic skin disease. The DNA/RNA Delivery Core of the Skin Biology & Diseases Resource-Based Center supports gene manipulation into skin cells through lentiviral and retroviral construct generation for researchers throughout Northwestern.

 Jaehyuk Choi Lab

Genetic basis of inherited and acquired immunological disorders and skin cancer.

Research Description

We employ cutting-edge genomics approaches to identify the genetic basis of inherited and acquired immunological disorders and skin cancer.

As an example, we have recently identified the genes and mutations underlying cutaneous T cell lymphoma, an incurable non-Hodgkin lymphoma of skin-homing T cells. The genes are components of the DNA damage, chromatin modifying, NF-kB and the T cell receptor signaling pathways. We are currently employing a comprehensive approach using human tissues and animal models to investigate the functions of these genes. We are confident these studies will allow us to elucidate the pathophysiology of this cancer and lead to the identification of novel therapeutic targets.

Work in the lab is funded by National Cancer Institute, Dermatology Foundation, American Skin Association and American Cancer Society. See the work of the Choi lab in the news. For further information, please also see Dr. Choi's faculty profile.

Publications

See Dr. Choi's publications on PubMed.

Contact

Contact Dr. Choi.

 Amy S. Paller Lab

a) Ganglioside modulation in diabetic wound healing and epidermal innervation abnormalities.

b) Impact of adiponectin on psoriasis severity and immunophenotype in obesity.

c) Utilizing siRNA and antisense Spherical Nucleic Acids (SNAs) to treat skin disorders.

Research Description

The Paller laboratory primarily focuses on inflammatory skin diseases and the development of novel therapeutic approaches. 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. The most recent translational research has involved use of ganglioside depletion using genetic and biochemical approaches to accelerate diabetic wound healing in human 3D and mouse diet-induced obese models, as well as to reverse the innervation abnormalities in back skin and footpads in 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. The Paller laboratory has 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, an intense focus of investigation is 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. SNAs for psoriasis have advanced to human trials.

Publications

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.

Faculty

Amy S. Paller, MD/MS

Senior Research Associate

Michael Bonkowski, PhD

Research Associate Professor

Xiao-Qi Wang, MD/PhD

Postdoctoral Fellows

Haoming Liu, PhD, Thomas Holmes, PhD

Visiting Predoctoral Fellow

Kevin Kwan

Technician

Kyle Dombeck

 June Robinson

Primary and Secondary Prevention of Melanoma

Systematic qualitative research examines the etiological behavioral process among at-risk subjects to inform the development of novel interventions to enhance sun protection, reduce deliberate indoor tanning and promote early detection of melanoma. The novel interventions are then examined in large-scale longitudinal clinical studies. We work with investigators from a variety of disciplines to develop and test the interventions. As an example, the research that developed an Internet-based culturally sensitive approach to sun protection counseling to prevent skin cancer in kidney transplant recipients formed a team consisting of experts in physician patient communications, a medical anthropologist, nephrologists and dermatologists.

The scope of our currently funded research could enhance melanoma detection by skin self-examination among the one million living melanoma patients who have a 10 times greater risk of developing melanoma than the general population.

Work in this dry laboratory is funded by the National Cancer Institute.

Publications

For publication information and more, see Dr. June K Robinson's Faculty Profile.

 Xiao-Qi Wang Lab

Investigates novel biomarkers for metastatic melanomas and related mechanisms.

Research Description

The Wang research team is focused on the discovery of novel biomarkers for melanoma metastasis along with the study of how these novel biomarkers regulate metastasis in melanomas. 

 Wang’s research has provided evidence of ganglioside alteration in skin cancers. Dr. Wang and her research team have shown that manipulating ganglioside content profoundly affects cell function through binding directly to glycosylated receptors, such the epidermal growth factor receptor (EGFR), integrin a5β1 and urokinase-like plasminogen activator receptor (uPAR).

Gangliosides are glycosphingolipids that regulate tumor metastasis and growth at the plasma membrane. The Wang research team has recently discovered that deacetylate GM3 (d-GM3) is exclusively expressed in metastatic melanomas, but not in primary melanomas and benign nevi, suggesting that d-GM3 is a novel biomarker for melanoma metastasis. GM3 is the simplest ganglioside. Native classic GM3 (c-GM3) is the predominant ganglioside in most normal human cells, while its’ variant, d-GM3 has not been found in normal human cells. In addition, d-GM3 is immunologically distinguishable from c-GM3, which enables us to specific target d-GM3 and minimizes potential toxicity to normal cells.

Dr. Wang’s team also found that d-GM3 expression increases melanoma proliferation, migration and survival and has linked GM3 deacetylation 

Publications

For publication information and more, see Xiao-Qi Wang’s, MD/PhD, faculty profile.

Contact Wang Lab

Contact the Wang Lab at 312-503-0294 or visit us on campus in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-070, Chicago, Illinois, 60611(housed in the Paller Lab).

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