Targeting p53-Dependent Repigmentation in Vitiligo

描述（由申请人提供）：这是一个K 01指导研究科学家发展奖的应用程序博士塔玛拉Terzian，博士后研究员在科罗拉多丹佛大学（UCD）。Terzian博士获得了免疫皮肤病学的培训奖，主题是“p53通路在黑色素瘤中的作用”，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肿瘤抑制剂领域的杰出研究人员。她对p53在发育和肿瘤发生中的基因剂量效应的研究，以及对突变型p53作用机制的揭示，在过去5年中在顶级期刊如Cell，The Journal of Clinical Investigation和Genes and Development以及其他16篇文章中发表了开创性的论文。她不得不搬到丹佛跟随她的丈夫，缩短了萌芽的职业生涯作为一个初级教员在UT MD安德森癌症中心。她现在正在将她的研究转向一个新的方向，研究p53诱导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导师委员会：Dennis Roop博士（基础研究部分的导师）、大卫诺里斯博士（转化研究部分的导师）、乔治科萨雷利斯博士（合作者）和卡罗琳勒普尔博士（合作者）。Roop博士是Charles C.盖茨中心再生医学和干细胞生物学（CRMSB）在UCD和皮肤病学教授。他的研究重点是遗传性皮肤病小鼠模型的产生和这些疾病的干细胞疗法的发展。Roop在UCD创造了一个出色的研究环境，Terzian拥有实验室和办公空间来进行研究，并获得最先进的设备和资源。Terzian博士还将接受Roop博士在基础研究方面的出色培训，Roop博士在培训和培养精英皮肤研究人员方面建立了出色的记录。诺里斯是UCD皮肤科系主任，也是免疫皮肤病学培训补助金和UCD皮肤病研究核心中心（UCD-SDRC）的主任，这两个中心都由NIAMS资助。诺里斯博士是一位著名的皮肤科医生和免疫皮肤病科学家，如白癜风和狼疮。Cotsarelis博士是宾夕法尼亚大学皮肤科系主任，是上皮干细胞分析专家，也是宾夕法尼亚大学SDRC资助的干细胞和异种移植核心的主任。这些技术对于实现本提案的目标至关重要，Cotsarelis博士已同意从Terzian博士的核心出发，对他进行这些技术的培训。Le Poole博士是皮肤和白癜风免疫疾病的专家。她在白癜风研究方面的专业知识对于设计和解释生成的数据将是非常宝贵的。这个指导团队是Terzian博士的建议和职业发展成功的理想选择。她计划研究p53通路在调节角质形成细胞分泌因子中的作用，以及这些因子如何影响黑素细胞的行为（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，并确定所涉及的关键因素。为了实现这一点，她将使用2种小鼠模型：1）表达高水平的p53并具有色素沉着过度的皮肤的煤烟足共济失调小鼠模型;色素沉着过度是白癜风的相反过程并模拟UV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调节并影响黑素细胞行为的角质形成细胞特异性因子（目的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 从第一个模型（目标1）。组织培养研究还将鉴定参与黑素细胞增殖、迁移和分化的基本角化细胞因子（Aim 2）。此外，将移植的人正常皮肤和白癜风（来自5名患者）皮肤的UV治疗与p53特异性因子进行比较，将建立后者作为替代疗法代替P53特异性因子的潜力。 基于UVB的传统疗法（目标3）。这种白癜风的色素沉着治疗是再生医学的一个经典例子，其中毛囊龛中的干细胞群的激活可以产生分化的黑素细胞，这些黑素细胞将重新填充毛囊间表皮并恢复正常的色素沉着。为了实现拟议的目标，Terzian博士将参加免疫学、皮肤病学和皮肤病理学、药理学、生物统计学和伦理学课程。这些课程将帮助Terzian博士进行皮肤研究培训，并为她作为白癜风科学家的独立职业做好准备。本研究产生的数据将在K奖结束前成为R 01资助申请的基础。 皮肤科，再生医学和干细胞生物学中心和指导委员会的部门都是一致的，以确保博士的科学成长和职业发展。Terzian博士将获得完成本提案目标所需的所有支持，建议和资源，预计将为白癜风提供新的见解 并导致这种毁灭性疾病的新治疗方法的发展。

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.