Targeting p53-Dependent Repigmentation in Vitiligo

靶向白癜风中 p53 依赖性重色素沉着

• 批准号: 8510581
• 负责人: Tamara G Terzian
• 金额: $ 10.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510581
• 关键词: Adverse effects; Affect; Animal Model; Apoptosis; Applications Grants; Area; Arts; Ataxia; Autoimmune Diseases; Award; Back; Basic Science; Behavior; Biological Assay; Biometry; Biopsy; Cancer Center; Cell Culture Techniques; Cell Cycle Arrest; Cell Death; Cell Therapy; Cells; Clinical Trials; Coculture Techniques; Color; Colorado; Complex; Cytotoxic T-Lymphocytes; DNA Repair; Data; Dermatologist; Dermatology; Dermatopathology; Development; Disease; Ensure; Environment; Epidermis; Epithelial; Equipment; Ethics; Evaluation; FGF2 gene; Faculty; Funding; Gender; Gene Dosage; Gene Expression; Generations; Genes; Goals; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Growth and Development function; Hair follicle structure; Health; Human; Husband; Hyperpigmentation; Immune; Immune System Diseases; Immunology; Incidence; Individual; Inflammatory; Inherited; Journals; K-Series Research Career Programs; KITLG gene; LIF gene; Lupus; Mediating; Medical; Mentored Research Scientist Development Award; Mentors; Mentorship; Modeling; Molecular; Molecular Analysis; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Pathology; Pathway interactions; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacology; Phototherapy; Pigmentation physiologic function; Pigments; Plant Roots; Population; Postdoctoral Fellow; Preclinical Testing; Procedures; Process; Proliferating; Protein p53; Proto-Oncogene Protein c-kit; Publications; Quality of life; Race; Radiation; Regenerative Medicine; Regimen; Replacement Therapy; Research; Research Personnel; Resources; Risk; Role; Scientist; Seminal; Signal Transduction; Skin; Skin Cancer; Skin graft; Skin tanning; Stem cells; Stimulus; Stress; System; TYR gene; Techniques; Technology; Testing; Therapeutic; Therapeutic Studies; Tissues; Training; UV Radiation Exposure; UV induced; UV response; Ultraviolet B Radiation; Ultraviolet Rays; Universities; Up-Regulation; Viola; Vitiligo; Xenograft Model; Xenograft procedure; base; career; career development; cell injury; conventional therapy; cytokine; design; direct application; drug development; drug testing; foot; insight; instructor; keratinocyte; laser capture microdissection; melanocyte; melanoma; member; migration; molecular marker; mouse model; mutant; novel therapeutic intervention; nutlin 3; paracrine; professor; psychologic; psychological distress; research study; skin disorder; skin patch; skin xenograft; social; stem; stem cell biology; stem cell population; success; therapeutic evaluation; tissue culture; transcription factor; tumorigenesis

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.

描述（由申请人提供）：这是科罗拉多大学丹佛大学（UCD）的博士后研究员塔玛拉·特齐安（Tamara Terzian）博士的K01指导研究科学家发展奖的申请。 Terzian博士已被授予免疫皮肤病学培训奖，该奖项将于2011年6月完成，该奖项将于2011年6月完成。她将在完成培训补助金后晋升为教练。 Terzian博士在一位国际知名的科学家Guillermina Lozano博士的指导下，在p53肿瘤抑制剂领域中成为杰出的研究员。她对p53在发育和肿瘤发生中的基因剂量作用以及发现突变体p53的作用机理的研究导致在诸如细胞，临床研究与基因和发展杂志等顶级期刊中的开创性出版物以及过去5年中其他16篇文章。她不得不搬到丹佛跟随丈夫，在UT MD Anderson Cancer Center担任初级教师的职业生涯迅速崭露头角。现在，她正在将研究朝着新的方向研究，以研究p53诱导的白癜风皮肤抑制作用的治疗潜力。为此，她选择了皮肤研究领域最好的指导委员会：Dennis Roop博士（基本研究的指导者），David Norris博士（研究的转化部分的导师），George Cotsarelis博士（合作者）和Caroline Le Poole博士（合作者）。 Roop博士是UCD的Charles C. Gates再生医学与干细胞生物学中心（CRMSB）的主任，也是皮肤病学教授。他的研究重点是遗传性皮肤疾病的小鼠模型以及这些疾病基于干细胞的疗法的发展。 Roop博士在UCD创建了一个杰出的研究环境，Terzian博士拥有实验室和办公空间，以进行研究并获取出厂设备和资源。 Terzian博士还将获得Roop博士的基础研究培训，后者在培训和发展精英皮肤研究人员方面取得了出色的记录。 Norris博士是UCD皮肤科部门的主席，也是免疫性皮肤病学培训补助金和UCD皮肤疾病研究核心中心（UCD-SDRC）的主任，两者均由NIAM资助。诺里斯博士是著名的皮肤科医生和免疫皮肤疾病的科学家，例如白癜风和狼疮。宾夕法尼亚大学皮肤病学系主席Cotsarelis博士是上皮干细胞分析的专家，宾夕法尼亚大学SDRC资助的干细胞和异种移植物核心的主任。这些技术对于完成该提案的目的至关重要，Cotsarelis博士同意从他的核心中培训Terzian博士。 Le Poole博士是皮肤和白癜风免疫疾病的专家。她在白癜风研究中的专业知识对于生成数据的设计和解释将是无价的。这个指导团队是Terzian博士的提议和职业发展成功的理想选择。她计划研究p53途径在调节角质形成细胞因素分泌方面的作用，以及这些因素如何影响黑素细胞行为（增殖，迁移和分化）。因此，她将检查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。为此，她将使用2种鼠标模型：1）表达高水平p53并具有色素沉重的皮肤；色素沉着是白癜风和模仿紫外线引起的人类皮肤晒黑的相反过程。因此，这种高p53小鼠模型将允许鉴定由p53调节并影响黑素细胞行为的角质形成细胞特异性因素（AIM 1）； 2）携带正常或白化皮肤的异种移植模型将有助于验证产生的数据 从第一个模型（在AIM 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质形成因子（AIM 2）。此外，比较接枝的人类正常和白癜风（从5例）皮肤与p53的特定因素进行比较，将确定后者作为替代疗法的潜力而代替 有风险的基于UVB的经典疗法（AIM 3）。这种对白癜风的抑制疗法是再生医学的一个经典例子，其中毛囊细胞中干细胞种群的激活可以产生分化的黑素细胞，从而重新填充际交流表皮并恢复正常的色素沉着。为了实现拟议的目的，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博士在皮肤研究方面进行培训，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构成K奖授予结束之前R01赠款申请的基础。 皮肤病学系，再生医学与干细胞生物学中心和指导委员会都均符合，以确保Terzian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，预计这些建议将提供新的见解 并导致这种毁灭性疾病的新型治疗方法的发展。