Targeting p53-Dependent Repigmentation in Vitiligo

描述(由申请者提供)：这是为科罗拉多大学丹佛分校博士后塔玛拉·特齐安博士申请K01指导研究科学家发展奖。Terzian博士已被授予“P53途径在黑色素瘤中的作用”免疫皮肤病学培训奖，该培训将于2011年6月完成。在完成培训补助金后，她将被提升为讲师。在国际知名科学家Guillermina Lozano博士的指导下，Terzian博士已成为p53肿瘤抑制基因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年里在《细胞》、《临床调查和基因与发育杂志》等顶级期刊上发表了开创性的文章和其他16篇文章。为了追随丈夫的脚步，她不得不搬到丹佛，结束了在UT MD安德森癌症中心担任初级教员的萌芽职业生涯。她现在正将她的研究带到一个新的方向，研究P53诱导的白癜风皮肤重新色素沉着的治疗潜力。为此，她选择了皮肤研究领域最好的导师委员会：丹尼斯·鲁普博士(研究基础部分的导师)、大卫·诺里斯博士(研究翻译部分的导师)、乔治·科萨雷利斯博士(合作者)和卡罗琳·勒普尔博士(合作者)。鲁普博士是加州大学查尔斯·C·盖茨再生医学和干细胞生物学中心(CRMSB)的主任和皮肤病教授。他的研究重点是遗传性皮肤病小鼠模型的建立，以及这些疾病基于干细胞的疗法的开发。Roop博士在UCD创造了一个出色的研究环境，Terzian博士在那里有实验室和办公室进行研究，并获得最先进的设备和资源。特齐安博士还将接受Roop博士在基础研究方面的出色培训，Roop博士在培训和开发精英皮肤研究人员方面建立了出色的记录。Norris博士是UCD皮肤科主任，也是免疫皮肤学培训基金和UCD皮肤病研究核心中心(UCD-SDRC)的主任，这两个中心都由NIAMS资助。诺里斯博士是一位著名的皮肤科医生和免疫性皮肤疾病的科学家，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，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中心的主任。这些技术对于实现这项提议的目标至关重要，Cotsarelis博士已同意从他的核心对Terzian博士进行这些技术培训。勒普尔博士是皮肤和白癜风免疫疾病方面的专家。她在白癜风研究方面的专业知识对于设计和解释产生的数据将是无价的。这个导师团队是Terzian博士求婚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方面的作用，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，并找出其中涉及的关键因素。为此，她将使用两个小鼠模型：1)高表达P53的煤油脚共济失调小鼠模型，皮肤色素沉着；与白癜风相反的是色素沉着，模仿紫外线诱导的人类皮肤晒黑；因此，这个高P53小鼠模型将允许识别受P53调控并影响黑素细胞行为的角质形成细胞特异性因子(目标1)；2)携带正常或白斑皮肤的异种移植模型将有助于验证所产生的数据 来自第一个模型(在目标1中)。组织培养研究还将确定与黑素细胞增殖、迁移和分化有关的基本角化因子(目标2)。此外，将紫外线治疗移植的正常人和白癜风(来自5名患者)的皮肤与P53特异性因子进行比较，将确定后者作为替代疗法的潜力。 高风险的经典UVB疗法(目标3)。这种治疗白癜风的重新着色疗法是再生医学的经典例子，在这种疗法中，毛囊壁龛中的干细胞群激活后可以产生分化的黑素细胞，这些细胞将重新填充毛囊间表皮，恢复正常的色素沉积。为了实现拟议的目标，特齐安博士将参加免疫学、皮肤病学和皮肤病理学、药理学、生物统计学和伦理学的课程。这些课程将帮助Terzian博士接受皮肤研究方面的培训，并为她作为白癜风科学家的独立职业生涯做好准备。这项研究产生的数据将成为K奖结束前R01赠款申请的基础。皮肤科、再生医学和干细胞生物学中心以及指导委员会都是一致的，以确保Terzian博士的科学成长和职业发展。Terzian博士将获得完成这项提案的目标所需的所有支持、建议和资源，预计这将为白癜风提供新的见解 并导致针对这种毁灭性疾病的新治疗方法的开发。

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.