Targeting p53-Dependent Repigmentation in Vitiligo

靶向白癜风中 p53 依赖性重色素沉着

• 批准号: 9097401
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097401
• 关键词: Adverse effects; Affect; Animal Model; Apoptosis; Applications Grants; Area; Arts; Ataxia; Autoimmune Diseases; Award; Back; Basic Science; Behavior; Biometry; Biopsy; Cancer Center; Cell Culture Techniques; Cell Cycle Arrest; Cell Death; Cell Therapy; Cells; Coculture Techniques; Color; Colorado; Complex; Cytotoxic T-Lymphocytes; DNA Repair; Data; Department chair; Dermatologist; Dermatology; Dermatopathology; Development; Disease; Ensure; Environment; Epidermis; Epithelial; Equipment; Ethics; Evaluation; FGF2 gene; Faculty; Funding; Gender; Gene Dosage; Gene Expression; Gene Expression Profiling; 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; TP53 gene; TYR gene; Techniques; Technology; Testing; Therapeutic; Therapeutic Studies; Tissues; Training; UV Radiation Exposure; UV induced; UV response; Ultraviolet B Radiation; Ultraviolet Rays; Ultraviolet Therapy; Universities; Up-Regulation; Viola; Vitiligo; Xenograft Model; Xenograft procedure; base; career; career development; cell injury; clinical investigation; 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培训奖，主题为“p53 通路在黑色素瘤中的作用”，该培训将于 2011 年 6 月完成。完成培训补助金后，她将晋升为讲师。在国际知名科学家 Guillermina Lozano 博士的指导下，Terzian 博士已成为 p53 肿瘤抑制领域的杰出研究员。她对 p53 在发育和肿瘤发生中的基因剂量效应的研究，以及揭示突变体 p53 的作用机制，已在《Cell》、《临床研究杂志》和《基因与发育杂志》等顶级期刊上发表了开创性的论文，并在最近发表了 16 篇其他文章5年。她不得不搬到丹佛跟随丈夫，从而终止了在 UT MD 安德森癌症中心担任初级教员的萌芽职业生涯。她现在正在将她的研究转向一个新的方向，以研究 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优秀的导师委员会：Dennis Roop 博士（基础研究部分的导师）、David Norris 博士（研究转化部分的导师）、George Cotsarelis 博士（合作者）和卡罗琳·勒普尔博士（合作者）。 Roop 博士是都柏林大学查尔斯·盖茨再生医学和干细胞生物学中心 (CRMSB) 的主任兼皮肤病学教授。他的研究重点是遗传性皮肤病小鼠模型的生成以及针对这些疾病的基于干细胞的疗法的开发。 Roop 博士在都柏林大学创造了出色的研究环境，Terzian 博士在这里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有着出色的记录。 Norris 博士是都柏林大学皮肤科系主任，也是免疫皮肤病学培训基金和都柏林大学皮肤病研究核心中心 (UCD-SDRC) 的主任，这两个中心均由 NIAMS 资助。诺里斯博士是白癜​​风和狼疮等免疫性皮肤病方面的著名皮肤科医生和科学家。 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。这些技术对于实现该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。 Le Poole 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生成数据的设计和解释非常宝贵。这个导师团队是 Terzian 博士的提案成功和职业发展的理想选择。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，并找出其中的关键因素。为了实现这一目标，她将使用 2 个小鼠模型：1) 煤烟足共济失调小鼠模型，该模型表达高水平的 p53 并具有色素沉着过度的皮肤；色素沉着过度是白癜风的相反过程，模仿紫外线引起的人类皮肤晒黑；因此，这种高 p53 小鼠模型将能够识别受 p53 调节并影响黑素细胞行为的角质形成细胞特异性因子（目标 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 来自第一个模型（目标 1）。组织培养研究还将鉴定参与黑素细胞增殖、迁移和分化的重要角质形成因子（目标 2）。此外，将移植的人类正常皮肤和白癜风（来自 5 名患者）皮肤的紫外线治疗与 p53 特异性因子进行比较，将确定后者作为替代疗法的潜力。 基于风险的经典 UVB 疗法（目标 3）。这种白癜风重新色素沉着疗法是再生医学的典型例子，其中毛囊微环境中的干细胞群的激活可以产生分化的黑色素细胞，这些黑色素细胞将重新填充毛囊间表皮并恢复正常色素沉着。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做好准备。本研究生成的数据将构成 K 奖结束前 R01 资助申请的基础。 皮肤科、再生医学和干细胞生物学中心以及指导委员会齐心协力，确保 Terzian 博士的科学成长和职业发展。 Terzian 博士将获得完成该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 并导致针对这种毁灭性疾病的新治疗方法的开发。

项目成果

Mutant p53 accumulates in cycling and proliferating cells in the normal tissues of p53 R172H mutant mice.

突变体p53在p53 R172H突变小鼠正常组织的循环和增殖细胞中积累。

• 发表时间: 2015-07-20
• 作者: Goh, Amanda M;Xue, Yuezhen;Leushacke, Marc;Li, Ling;Wong, Julin S;Chiam, Poh Cheang;Rahmat, Siti Aishah Binte;Mann, Michael B;Mann, Karen M;Barker, Nick;Lozano, Guillermina;Terzian, Tamara;Lane, David P
• 通讯作者: Lane, David P

Targeting p53 in melanoma.

靶向黑色素瘤中的 p53。

• 发表时间: 2014-01
• 影响因子: 4.3
• 作者: Box, Neil F;Vukmer, Tyler O;Terzian, Tamara
• 通讯作者: Terzian, Tamara

Genetics of ribosomal proteins: "curiouser and curiouser".

核糖体蛋白的遗传学：“越来越好奇”。

• 发表时间: 2013
• 影响因子: 4.5
• 作者: Terzian, Tamara;Box, Neil
• 通讯作者: Box, Neil

A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection.

KIT 配体中的多态性 p53 反应元件会影响癌症风险并经历自然选择。

• 发表时间: 2013-10-10
• 影响因子: 64.5
• 作者: Zeron;Wang, Xuting;Repapi, Emmanouela;Campbell, Michelle R;Su, Dan;Castro;Davies, Benjamin;Peterse, Elisabeth F P;Sacilotto, Natalia;Walker, Graeme J;Terzian, Tamara;Tomlinson, Ian P;Box, Neil F;Meinshausen, Nico
• 通讯作者: Meinshausen, Nico