Research Overview The following are a sampling of research studies currently being conducted in the Department of Dermatology: Alice Pentland, M.D. Research in the Pentland Lab addresses the role of prostaglandins in skin carcinogenesis and in cell differentiation. The role of these lipid mediators in the induction of squamous cell carcinoma of the skin is being studied in the context of ultraviolet light injury. Recent work has shown that significant contributions to tumor initiation and promotion may be made by eicosanoids (arachidonic acid and its metabolites). Most importantly, non-steroidal anti-inflammatory drugs (NSAIDs), which are inhibitors of prostaglandin synthesis, have been shown to have anti-tumor properties in humans. Unfortunately, NSAIDs chemoprevention is limited by NSAID side effects. However, new data shows the hormone metabolizing enzyme aldoketoreductase AKR1C3 is also inhibited by most NSAIDs, begging the question whether cyclooxygenase inhibition is actually the key target through which NSAIDs produce their cancer prevention effects. A potential role in cancer for AKR1C3 has been shown in many tumor types. AKR1C3 metabolizes the cyclooxygenase product PGH2 into PGF2α, as well as transforming PGD2 into 9α11βPGF2. This activity can shunt prostaglandin metabolism away from pro-differentiation, pro-apoptotic mediators such as PGJ2. AKR1C3 is also the primary enzyme responsible for synthesis of 17β-estradiol and testosterone from their respective less active precursors, supporting its role in hormone sensitive tumors. Lastly, AKR1C3 is capable of supporting redox cycling, which can produce mutations that could promote carcinogenesis. We are testing the hypothesis that AKR1C3 is an important therapeutic target regulating SCC growth, due to PGF2α mediated signaling, redox and hormonal metabolic effects on SCC apoptosis, proliferation or invasion. We seek to determine whether this action is distinct from cancer reduction produced by cyclooxygenase. Current work addresses whether AKR1C3 expression is correlated with degree of tumor malignancy, and examines the relative importance of prostanoid metabolism, hormones and oxidative stress in human SCC-derived cell lines. In vivo models are also in use to understand the relative importance of these AKR1C3 activities. Lisa A. Beck, M.D. Dr. Beck's research interests are in three interrelated areas. First, we are interested in characterizing the epithelial tight junction defects at the molecular level in atopic dermatitis, the most common inflammatory skin disease in man. Numerous projects radiate from that central theme and include – 1) how do these defects differ in other inflammatory skin diseases such as chronic urticaria, psoriasis, CTCL, 2) what effects do various pharmacologic agents have on TJ function and structure, 3) can protease containing allergens or microbes affect TJ function and if so how. A second area of focus is evaluating the magnitude and character of the microbial responsiveness of keratinocytes (cutaneous epithelial cells) from atopic dermatitis subjects compared to nonatopic healthy controls. When differences are noted we are trying to determine the basis for these differences and believe this line of inquiry may explain AD subjects' susceptibility to colonization and infection with numerous bacteria, viruses and even yeast. Our third area has been to understand why there is such a paucity of tissue neutrophils in lesions from subjects with atopic dermatitis. These studies are not as advanced but suggest that there are phenotypic differences in AD neutrophils' responsiveness to the potent chemoattractant, IL-8 (CXCL8) compared to nonatopic controls. Lisa DeLouise, Ph.D. The overall research area in the laboratory is the creation of Smart Bandage Biomaterial Engineering and Skin Disease. This laboratory investigates the fundamental optical, morphological, and surface chemical properties of bioengineered nanoporous silicon (PSi) in developing a platform of Smart Bandage technologies targeting biosensors for point of care diagnosis of cutaneous disease, transdermal drug delivery, and tissue engineering for wound healing. PSi is fabricated from single crystal silicon wafers using an electrochemical etch process. The pore diameter, porosity (surface area and internal void volume), bioerosion, and interferometric optical properties can be tailored over a wide range to suit the application. Ongoing projects involve developing a refractive index sensitive biosensor for detection of Candida ablicans for which we've developed methods to site direct the immobilization of phage display scFv antibody receptors. Tests are underway to evaluate detection sensitivity relative to nonspecifically immobilized whole IgG aCandida antibody receptor employing commercial antigen. Fundamental insights into the factors (pore size, steric crowding, operating frequency, device architecture, blocking agent, operation protocol, etc.) that impact detection sensitivity are being explored. Biosensor tests are typically conducted on devices attached to the silicon wafer. Recently, we developed methods to detach the sensor and mount it in a polymer support. We are conducting studies to characterize the diffusion characteristics of small molecules though hydrogel films (40 micron) cast over porous silicon sensor (4 um) by monitoring changes in the optical response that result when molecules diffuse in or out of the porous silicon layer. This work will enable us to develop models for designing transdermal drug delivery systems where the optical response can be measured, while applied to the skin, to monitor the time released delivery of therapeutics concentrated within the porous reservoir. We are interested in developing a smart bandage to deliver antifungal locally to the nail matrix where nail progenitor cells live. We are also investing the morphology and phenotype dermal human fibroblast and immortalized keratinocytes (HaCaT) cells cultured on chemically modified PSi and flat silicon wafer surfaces. The goal is systematically engineer the surface chemistry, energy and topography of biomaterial scaffolds to mimic the fetal reepithelialization process. Our hypothesis is that by controlling differential cell proliferation (keratinocyte vs. fibroblast) and cell phenotype, such as integrin and metalloproteinase expression profiles or the magnitude of actin fiber extensions, novel therapies will result that can accelerate the healing of chronic wounds (ulcers) and burns with reduced scarring. A unique aspect of this research program is the melding of cross-disciplinary skills in surface science, physical chemistry, microfluidic device engineering, optics, and biological and medical sciences. This interdisciplinary approach provides a firm basis for the investigation and fabrication of new biomedical devices, while enabling a broader perspective on quantifying biological efficacy and establishing clinical utility. Mary Gail Mercurio, M.D. Dr. Mary Gail Mercurio is the Clinical Director in the Department of Dermatology at the University of Rochester Medical Center in Rochester, New York. She is the primary clinical attending in the department. She also heads the dermatology curriculum for first- and second-year medical students at the University of Rochester. Dr. Mercurio's clinical interests in dermatology have focused on skin and hair disorders afflicting women with particular interest in the hormonal effects of hyperandrogenism. She works closely with obstetrics and gynecology colleagues collaborating in a joint clinic for women with a variety of skin conditions, including vulvar skin disorders and those rashes that are unique to pregnancy. She is the director of the dermatology clinical trials unit, and is actively participating in trials pertaining to psoriasis, vulvar dermatitis, and melanoma. Her research is supported in part by the National Institutes of Health. Benjamin Miller, Ph.D. Research in the Miller group focuses on two fundamental areas: the control of biomolecular interactions through the synthesis of new small-molecule probes, and the observation of biomolecular interactions through the development of novel optical sensing technologies. In the area of control, we are particularly interested in the sequence-selective recognition of RNA. New RNA sequences with important functions in basic biology and human health and disease are being discovered at an ever-increasing rate, and yet our ability to target these sequences specifically is still at a rudimentary stage. To address this gap, we are applying techniques of molecular design and a novel combinatorial method of small-molecule evolution called Dynamic Combinatorial Chemistry, which allows us to rapidly "prototype" sequence-selective RNA binding molecules. Thus far we have used this methodology to RNA targets important in Myotonic Dystrophy and HIV. Protein-targeted small-molecule discovery projects are also of interest, and current projects include the mechanism of tight junction formation and the transport of beta-amyloid across the blood-brain barrier. To the end of achieving better methods of observing biomolecular interactions, our group has a longstanding program in the use of the optical properties of nanostructured materials as the basis for new biosensors and diagnostic tools. Two examples of current efforts include Arrayed Imaging Reflectometry (AIR) and sensors based on two-dimensional photonic crystals (2-D PhC). AIR relies on the creation of a near-perfect antireflection coating on the surface of a silicon chip; binding of a biomolecular target destroys this antireflective condition and is visible by a change in reflected light. This allows for highly multiplexed (10's to 1000's of targets) and quantitative detection. Photonic crystal sensors, on the other hand, offer the possibility of ultrasensitive detection: for example, a major long-term goal of our work is the production of sensors that can effectively detect one virus in a blood sample. Art Papier, M.D. Art Papier, M.D. is an Associate Professor in Dermatology and Medical Informatics at the University of Rochester. Dr. Papier specializes in contact and occupational dermatitis and has a special interest in acute skin rashes and skin presentations of infectious disease. His research focuses on point of care reference systems for physicians and Internet based medical information for patients. He is particularly interested in the topic of diagnostic errors in medical decision making and decision support systems. Dr. Papier was the PI of a NIAMS/NIH contract to develop a comprehensive dermatology lexicon. This work has transitioned to the American Academy of Dermatology as DermLex. Dr. Papier also is Chief Scientific Officer of Logical Images, the developer of VisualDx and an Internet self-paced course in dermatology education. Brian Poligone, M.D., Ph.D. The Poligone Laboratory studies signal transduction in the skin, specifically examining the role of the transcription factor NF kappa B in skin physiology and disease. Using genetic animal models to study the function of NF kappa B, we strive to better understand the molecular mechanisms behind skin inflammation and carcinogenesis. By studying animal models of disease, we are better able to translate our findings into clinically relevant treatments for human disease. Through his past work with Drs. Albert S. Baldwin and Sankar Ghosh, Dr. Poligone has gained expertise in the study of NF kappa B and has focused his attention to the skin. Currently we are examining how NF kappa B is involved in the formation of a type of skin cancer called a keratoacanthoma. Dr. Poligone has also examined the role of NF kappa B in psoriasis and specifically has been examining NF kappa B inhibitors in this disease. Julie Ryan, Ph.D., MPH Dr. Ryan performs basic and clinical research combining the fields of cancer control, dermatology, and radiation oncology. Dr. Ryan’s research primarily focuses on uncovering the biological mechanisms of radiation-induced skin toxicities and developing a successful intervention to reduce these toxicities and improve the quality of life of cancer patients. Radiation dermatitis occurs in about 95% of patients and can negatively affect a patient’s quality of life due to pain and premature interruption of radiation treatment. Management of radiation dermatitis has a broader significance as well; it has great importance in the morbidity and mortality expected in any potential “dirty bomb” attack. Curcumin, a component of turmeric, is a potent antioxidant and anti-inflammatory agent. It has been used for many years to treat skin ailments and is currently being used as an anti-cancer agent. Preclinical studies by our group demonstrated that curcumin (oral administration) reduced radiation skin toxicity by 50% in mice. Currently, Dr. Ryan has preclinical laboratory studies and clinical trials examining the role of skin barrier dysfunction and reactive oxygen species (ROS) in the severity of radiation skin injury and testing the efficacy of curcumin (both oral and topical administration) as a mitigator of radiation skin injury. As part of the Center for Medical Countermeasures Against Radiation (U19) Program Grant, Dr. Ryan is investigating the hypothesis that radiation-induced skin injury involves altered barrier function, haphazard dendritic cell trafficking, and reactive oxygen species (ROS)-mediated damage resulting in chronic inflammation and impeded wound healing. The clarification of the nature of these defects will provide a foundation for mitigating multi-organ damage from radiation. Furthermore, Dr. Ryan performs preclinical testing on other radioprotective/mitigative agents to reduce tissue injury while enhancing the sensitization of tumors to radiation. Additionally, Dr. Ryan is also interested in elucidating the potential physical and psychosocial factors that influence the frequency and severity of skin problems and pain experienced by cancer patients undergoing radiation treatment. She is currently performing a clinical study to test a new survey instrument designed to assess the skin problems and pain experienced by cancer patients undergoing radiation treatment. Besides radiation-induced skin injury, Dr. Ryan is also involved in studies examining ginger as an intervention for chemotherapy-related nausea. After a successful multisite clinical trial through the URCC Community Clinical Oncology Program (CCOP) demonstrated that ginger supplementation (i.e., capsules) significantly reduced acute chemotherapy-induced nausea in cancer patients receiving standard antiemetics during chemotherapy, Dr. Ryan has designed a pilot clinical trial to determine if ginger-scented nasal strips (Aromainhaler®) will be effective against chemotherapy-induced nausea. Glynis Scott, M.D. There are two major projects on going in my laboratory—the first is the investigation into signaling pathways of prostaglandins in human melanocytes and melanoma, and the second is the role of Plexin receptors in melanocyte and melanoma biology. Melanocytes are pigment producing cells within the epidermis that are progenitor cells for a deadly cancer, melanoma. The production of melanin by melanocytes is a key function of melanocytes and provides photoprotection to the skin. Prostaglandins (PG) are lipid signaling molecules released by keratinocytes and melanocytes in response to ultraviolet irradiation. Our research focus is on defining signaling intermediates that mediate the effect of the two primary PG in the skin, PGE2 & PGF2?? on melanocyte dendrite extension, growth and pigment production. Our laboratory is also investigating the role of sempahorins and their receptors on melanocyte growth, differentiation, and progression to melanoma. Semaphorins are membrane bound and secreted proteins involved in neuronal pathfinding, that we have recently shown to be involved in melanocyte adhesion and dendrite formation. Our particular focus is on Semaphorin 7A and Semaphorin 4D, and their cognate receptors Plexin C1 and Plexin B1, which are lost during progression of melanocytes to melanoma. Integration of signaling intermediates with biologic functions such as proliferation, apoptosis and migration, allow us to dissect the function of PG and semaphorins in melanocyte, and to link signaling by specific receptors to downstream biologic targets important for skin pigmentation and melanoma progression. Francisco Tausk, M.D. Classical Conditioning in the Pharmacotherapy of Psoriasis: Placebo arms are required in clinical trials in order to evaluate the non-specific effects of drug administration. One mechanism by which these are believed to work is Classical Conditioning. Our hypothesis is that patients exposed to a successful treatment, will subsequently benefit from the administration of a placebo through the mechanism of expectancy. We are conducting a study in which subjects with severe psoriasis will be treated with cyclosporine until remission, at which point we will maintain them clear with significantly lower doses of the drug by interspersing placebo with their schedule of cyclosporine.