Targeting p53-Dependent Repigmentation in Vitiligo

描述（由申请人提供）：这是科罗拉多大学丹佛分校（UCD）博士后Tamara Terzian博士的K01指导研究科学家发展奖申请。Terzian博士已获得免疫皮肤病学“p53通路在黑色素瘤中的作用”培训奖，该培训将于2011年6月完成。她将在完成培训补助金后晋升为讲师。Terzian博士在国际知名科学家Guillermina Lozano博士的指导下，成为p53肿瘤抑制领域的杰出研究员。在过去的5年里，她对p53基因剂量在发育和肿瘤发生中的作用以及突变型p53的作用机制的研究，在Cell、the Journal of Clinical Investigation和Genes and development等顶级期刊上发表了16篇开创性的论文。她不得不跟随丈夫搬到丹佛，结束了在德州大学安德森癌症中心担任初级教员的职业生涯。她现在正在研究一个新的方向，研究p53诱导的白癜风皮肤色素沉着的治疗潜力。为此，她选择了皮肤研究领域最优秀的指导委员会：Dennis Roop博士（基础部分研究导师）、David Norris博士（转化部分研究导师）、George Cotsarelis博士（合作者）和Caroline Le Poole博士（合作者）。Roop博士是UCD查尔斯·盖茨再生医学和干细胞生物学中心（CRMSB）的主任和皮肤学教授。他的研究主要集中在遗传性皮肤疾病的小鼠模型的产生和干细胞为基础的治疗这些疾病的发展。鲁普博士在UCD创造了一个优秀的研究环境，在那里Terzian博士有实验室和办公空间来进行她的研究，并获得最先进的设备和资源。Dr. Terzian还将从Dr. Roop那里接受基础研究方面的优秀培训，Dr. Roop在培训和培养精英皮肤研究人员方面有着出色的记录。Norris博士是UCD皮肤科主任，也是免疫皮肤病学培训基金和UCD皮肤病研究核心中心（UCD- sdrc）的主任，这两个中心都是由NIAMS资助的。诺里斯博士是一名著名的皮肤科医生和科学家，研究免疫皮肤疾病，如白癜风和狼疮。Cotsarelis博士是宾夕法尼亚大学皮肤病学系主任，上皮干细胞分析专家，宾夕法尼亚大学sdrc资助的干细胞和异种移植中心主任。这些技术对于实现本提案的目标至关重要，Cotsarelis博士已同意对Terzian博士进行核心技术培训。勒普尔博士是皮肤免疫疾病和白癜风方面的专家。她在白癜风研究方面的专业知识对于所生成数据的设计和解释将是无价的。这个导师团队对Terzian博士的提案和职业发展的成功是理想的。她计划研究p53通路在调节角质形成细胞因子分泌中的作用，以及这些因子如何影响黑素细胞行为（增殖、迁移和分化）。因此，她将研究p53激活对正常皮肤色素沉着过程的影响，并确定其中的关键因素。为了实现这一目标，她将使用两种小鼠模型：1)表达高水平p53且皮肤色素沉着的黑足共济失调小鼠模型；色素沉着是白癜风的相反过程，模仿紫外线诱导的人类皮肤晒黑；因此，这种高p53小鼠模型将允许鉴定受p53调控并影响黑素细胞行为的角化细胞特异性因子（Aim 1）；2)携带正常或白癜风皮肤的异种移植模型将有助于验证生成的数据

DESCRIPTION (provided by applicant): 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.