This is an application for a K01 Mentored Research Scientist Development Award for Dr. Tamara Terzian, a postdoctoral fellow at the University of Colorado Denver (UCD). Dr Terzian has been granted a training award in Immunodermatology on """"""""The role of p53 pathway in melanoma"""""""" that will be completed in June 2011. She will be promoted to Instructor upon completion of the training grant. Dr. Terzian has established herself as an exceptional researcher in the p53 tumor suppressor field under the mentorship of an internationally renowned scientist, Dr. Guillermina Lozano. Her studies on gene dosage effects of p53 in development and tumorigenesis and uncovering the mechanism of action of mutant p53 have resulted in seminal publications in top tier journals such as Cell, The Journal of Clinical Investigation and Genes and Development and 16 other articles in the last 5 years. She had to move to Denver to follow her husband, cutting short a budding career as a junior faculty member at UT MD Anderson Cancer Center. She is now taking her research in a new direction to study the therapeutic potential of p53-induced repigmentation in vitiligo skin. For this, she chose her mentoring committee among the best in the skin research field: Dr. Dennis Roop (mentor of the basic part of research), Dr. David Norris (mentor of the translational part of research), Dr. George Cotsarelis (collaborator), and Dr. Caroline Le Poole (collaborator). Dr. Roop is the Director of the Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology (CRMSB) at UCD and Professor of Dermatology. His research focuses on the generation of mouse models of inherited skin disorders and the development of stem cell-based therapies for these diseases. Dr. Roop has created an outstanding research environment at UCD where Dr. Terzian has lab and office space to conduct her research and access to state-of-art equipment and resources. Dr. Terzian will also receive excellent training in basic research from Dr. Roop, who has established an outstanding track record in training and developing elite skin researchers. Dr. Norris is the Chair of the Dermatology Department at UCD and the director of the Training Grant in Immunodermatology and the UCD Skin Diseases Research Core Center (UCD-SDRC), both of which are funded by NIAMS. Dr. Norris is a renowned dermatologist and scientist in immune skin disorders, such as vitiligo and lupus. Dr. Cotsarelis, Chair of the Department of Dermatology at University of Pennsylvania, is an expert in epithelial stem cell analysis and director of the University of Pennsylvania SDRC-funded Stem Cell and Xenografts Core. These technologies are essential for the accomplishment of the aims of this proposal, and Dr Cotsarelis has agreed to train Dr. Terzian in these techniques from his core. Dr. Le Poole is an expert in immune diseases of skin and vitiligo. Her expertise in vitiligo research will be invaluable for the design and the interpretation of the generated data. This mentorship team is ideal for the success of Dr. Terzian's proposal and career development. She plans to investigate the role of the p53 pathway in regulating the secretion of factors from keratinocytes and how these factors affect melanocyte behavior (proliferation, migration and differentiation). Therefore, she will examine the impact of p53 activation on the pigmentation process of normal skin and identify the key factors involved. To accomplish this, she will use 2 mouse models: 1) The Sooty Foot Ataxia mouse model which expresses a high level of p53 and has a hyperpigmented skin;hyperpigmentation is the opposite process of vitiligo and mimics UV-induced human skin tanning;thus, this high p53 mouse model will allow the identification of keratinocyte-specific factors that are regulated by p53 and influence melanocyte behavior (Aim 1);2) a xenograft model carrying normal or vitiligenous skin will help validate the data generated from the first model (in Aim 1). Tissue culture studies will also identify the essential keratinocye factors involved in melanocyte proliferation, migration and differentiation (Aim 2). In addition, comparing UV treatment of the grafted human normal and vitiligo (from 5 patients) skin to the p53 specific factors will establish the potential of the latter as a replacement therapy in lieu of the risky classical UVB based therapy (Aim 3). This repigmentation therapy for vitiligo is a classic example of regenerative medicine where activation of a stem cell population in a hair follicle niche can produce differentiated melanocytes that will repopulate the interfollicular epidermis and restore normal pigmentation. To accomplish the proposed aims, Dr. Terzian will attend courses in immunology, dermatology and dermatopathology, pharmacology, biostatistics and ethics. These courses will assist Dr. Terzian in her training in skin research and prepare her for an independent career as a vitiligo scientist. The data generated by this study will form the basis for an R01 grant application before the end of the K award. The Department of Dermatology, the Center for Regenerative Medicine and Stem Cell Biology and the mentoring committee are all aligned to ensure the scientific growth and career development of Dr. Terzian. Dr. Terzian will be provided with all of the support, advice and resources necessary for the completion of the aims of this proposal, which are anticipated to provide new insight into vitiligo and result in the development of novel therapeutic approaches for this devastating disease.

Public Health Relevance

Vitiligo is a complex skin disease that causes white skin patches. It affects 1% of world's population independent of race or gender but particularly impacts people of color since the darker skin contrasts with the white patches. Thus, the affected individuals suffer from psychological distress and feel stigmatized by their condition. Conventional treatment for vitiligo includes phototherapy (UVB) based repigmentation which presents with significant health risks, such as an increased incidence of skin cancer. The purpose of this proposal is to dissect the molecular mechanisms that underpin repigmentation by using a hyperpigmented mouse model and a human skin grafting system on the back of mice in combination with intricate cell culture and drug testing procedures. Our ultimate goal is to exploit these findings to demonstrate a safer and more effective replacement therapy for the traditional UV radiation regimen.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Cibotti, Ricardo
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University of Colorado Denver
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United States
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Filipp, Fabian V; Birlea, Stanca; Bosenberg, Marcus W et al. (2018) Frontiers in pigment cell and melanoma research. Pigment Cell Melanoma Res 31:728-735
Joselow, Andrew; Lynn, Darren; Terzian, Tamara et al. (2017) Senescence-Like Phenotypes in Human Nevi. Methods Mol Biol 1534:175-184
Shellman, Yiqun G; Lambert, Karoline A; Brauweiler, Anne et al. (2015) SASH1 Is Involved in an Autosomal Dominant Lentiginous Phenotype. J Invest Dermatol 135:3192-3194
Goh, Amanda M; Xue, Yuezhen; Leushacke, Marc et al. (2015) Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice. Oncotarget 6:17968-80
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BarĂ³n, Anna E; Asdigian, Nancy L; Gonzalez, Victoria et al. (2014) Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes. Cancer Epidemiol Biomarkers Prev 23:2829-39
Terzian, Tamara; Box, Neil (2013) Genetics of ribosomal proteins: ""curiouser and curiouser"". PLoS Genet 9:e1003300
Zeron-Medina, Jorge; Wang, Xuting; Repapi, Emmanouela et al. (2013) A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell 155:410-22