2016 UW Skin Disease Research Center Pilot Awards
The recipients of the 2016 SDRC Pilot and Feasibility Awards Program have been announced. Below are the innovative projects receiving support beginning 09/01/2016:
PI: Paul Lambert, PhD, UW School of Medicine & Public Health, Oncology
Title: Role of Immunosuppression in Papillomavirus-induced Skin Disease
Papillomaviruses (PVs) are double stranded DNA viruses that infect epithelia of their natural host. Recently the first papillomavirus to infect laboratory mice, MmuPV1, was discovered in a vivarium in India. During our first year of pilot support we carried out studies using delayed type hypersensitivity assays that demonstrated a strong correlation between the ability of UVR to induce systemic immunosuppression and its ability to make mice susceptible to MmuPV1-induced warts, with our results published in PLOS Pathogens. We have preliminary evidence to show there is increased susceptibility to MmuPV1-induced warts in two mouse models of human immunodeficiency syndromes; X-Scid patients (IL2Rγ-deficient mice) and MonoMAC (GATA2 heterozygous mutant mice, in collaboration with Emery Bresnick). We are now acquiring mice from Dr. Francoise Bachelorie in France that model human WHIM syndrome (CXCR4 mutant mice). These mice carry an amino acid substitution in CXCR4 that leads to increased CXCL12/CXCR4-dependent signaling, a hallmark of WHIM patients that contributes to the observed leukopenia in these patients. However, our colleague in France has also learned that activation of this signaling axis directly contributes to HPV-induced hyperplasia, raising the possibility of a role of CXCR4/CXCL12 signaling in wart formation that may be distinct from its effects on the immune system. During our second year of SDRC funding we propose to complete our initial studies on these mouse models and plan to generate a second generation WHIM mouse model to further dissect the role of CXCR4/CXCL12 signaling in increasing susceptibility of patients to HPV infection.
PI: Emery Bresnick, PhD, UW School of Medicine & Public Health, Cell and Regenerative Biology
Title: New Mode of Controlling Stem Cell Factor-c-Kit Signaling
Deregulated signaling by the receptor tyrosine kinase c-Kit underlies cutaneous mastocytosis, a small subset of malignant melanoma, and a battery of non-malignant and malignant hematopoietic disorders. In addition to uncontrolled proliferation of mast cells, deregulated c-Kit signaling drastically alters mast cell functionality at tissue sites, including skin. In the initial year of this pilot project, we made progress on dissecting the mechanism by which Samd14 controls c-Kit signaling and developed fundamental methodology required to study this new mechanism in primary mast cells. These studies will solidify a new paradigm of SCF-c-Kit signaling and will lay a foundation for devising new strategies to antagonize c-Kit for the treatment of pathological disorders resulting from deregulated c-Kit signaling.
PI: Jean Christopher Chamcheu, PhD, UW School of Medicine & Public Health, Dermatology
Title: Development and validation of a novel full-thickness three-dimensional (3D) Human Skin Equivalent Model of Psoriasis (FTRHSP)
Psoriasis is a chronic and incurable inflammatory skin disease that affects an estimated 7.5 million Americans. Its etiology is incompletely understood but involves a complex interaction between the immune system and the skin. This proposal is designed to develop a full-thickness three-dimensional (3D) reconstituted human skin equivalent model of psoriasis (FTRHSP) that recapitulates both the epidermal hyperplasia and inflammatory features of psoriasis. Successful completion of this proposal may result in the development of a useful in vitro tissue regenerated 3D reconstituted human skin model of psoriasis, a strategy mimicking psoriatic disease that could be useful for the rapid screens of drugs for the treatment of psoriasis, and possibly other hyperproliferative keratinizing and autoimmune skin disorders.
PI: Christopher Bradfield, PhD, UW School of Medicine & Public Health, Oncology
Title: The Aryl Hydrocarbon Receptor in Inflammatory Skin Disorders
Recent advances in our understanding of the pathogenesis underlying inflammatory skin conditions such as psoriasis or atopic dermatitis have highlighted involvement of the ligand-activated transcription factor, aryl hydrocarbon receptor (AHR). This project will investigate strategies that may increase the efficacy of AHR ligands in treatment of psoriasis and to identify cellular and molecular targets of different classes of AHR ligands.
PI: Stefan Schieke, PhD, UW School of Medicine & Public Health, Dermatology
Title: Role of the slow-cycling, stem-like T-cell phenotype in early-stage cutaneous T-cell lymphoma compared to benign inflammatory skin disease.
In this study, we want to focus on the role of slow-cycling, stem-like T-cells in early stages of CTCL and the potential evolution from (benign) inflammatory infiltrates. Furthermore, we want to study the phenotypic relationship between slow-cycling states in neoplastic and normal T-cells. The first aim of the project is comparative transcriptome analysis of phenotypic markers of slow-cycling states in normal and neoplastic T-cells. The second aim is the characterization of slow-cycling phenotypes in human samples of benign inflammatory dermatoses and cutaneous T-cell lymphoma. Successful completion of the proposed experiments will determine the specificity of phenotypic markers for the slow-cycling subpopulation among neoplastic compared to normal T-cells.
PI: Angela Gibson, MD, PhD, UW School of Medicine & Public Health, Surgery
Title: Molecular and proteomic signatures of cellular regeneration in burn tissue.
The focus of this pilot proposal is to characterize the gene expression associated with cell death, regeneration and differentiation in skin after burn injury. We hypothesize that burn wounds possess regenerative capacity for re-epithelialization in the viable dermal and subcutaneous tissue that is unrecognized using current surgical techniques. Preserving viable tissue serves to increase the cellular substrate from which regeneration may occur. Understanding the molecular and proteomic signatures of deep partial thickness and full thickness burns may lead to the development of surgical techniques focused on preserving viable tissue and therapeutic options such as biologic dressings aimed at optimizing regenerative capacity. We propose an innovative method of utilizing RNA-Seq to characterize the regenerative capacity of injured tissue from burn patients ex vivo.
ICTR co-funding of 2016 UW Skin Disease Research Center Pilot Awards
In partnership with the UW Institute for Clinical and Translational Research (ICTR), we are pleased to announce two awards receiving co-funding support:
PI: Nancy Keller, PhD, UW School of Medicine & Public Health, Medical Microbiology and Immunology
Title: Synthetic Polymers to Target Dermatophytic Fungi
It is estimated that cutaneous fungal infections account for over 4 million outpatient visits annually in USA and estimates of the cost of treating fungal skin infections vary from $500 million to $1.7 billion annually in the United States. We have recently discovered a new class of synthetic polymers that are active against invasive human fungal pathogens and show little toxicity against human cells. Here we propose to examine the efficacy of these polymers against dermatophytic species and initiate an exploration of their mode(s) of action.
PI: Parameswaran Ramanathan, PhD, UW College of Engineering, Electrical and Computer Engineering;
Vijayasaradhi Setaluri, PhD, UW School of Medicine & Public Health, Dermatology
Title: Characterization of Regulatory Mechanisms of MITF in Melanocytes
Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocytes with a central role in its survival and differentiation. The first aim of this project is to significantly improve our understanding of MITF-related regulatory mechanisms using recently developed novel computational methods that can better elucidate the binding specificities of transcription factors (TFs) such as MITF. The second aim of the project is to experimentally validate the potential regulatory mechanisms identified using the new computational methods. These new computational methods have the potential to identify novel regulatory mechanisms of considerable importance to skin disease research.