Defining T helper cell associated cytokines and mechanisms in Alopecia Areata

 描述（由申请人提供）：本K 08提案详细介绍了阿里·贾巴里博士在皮肤病学基础和转化研究方面的职业发展的全面五年计划。Jabbari博士是哥伦比亚大学皮肤科的早期职业医生科学家。Jabbari博士先前的临床和研究经验使他在研究斑秃（AA）方面处于独特的地位，斑秃是一种自身免疫性疾病，毛囊是攻击的目标。尽管其患病率很高，但AA没有循证治疗。在C3 H/HeJ AA小鼠模型中的研究表明，AA的发展严重依赖于T辅助细胞1（Th 1）相关细胞因子干扰素-γ，并且对有限数量的AA人类受试者皮肤中的基因表达特征的初始基于微阵列的评估鉴定了显著干扰素特征的存在。Jabbari博士的建议涉及IL-12（一种典型的Th 1细胞因子）在AA发病机制中的作用。此外，他将比较AA的转录谱，从国家斑秃登记处收集的数十个样本中产生，从原型Th相关的炎症性皮肤病中获得的可用谱。在该提案中，Jabbari博士建议（i）使用AA的遗传模型评估IL-12在AA发展中的作用，（ii）评估抗IL- 12或抗IL-12 R抗体在AA治疗中的用途，以及（iii）对人类AA与原型Th相关皮肤病和IL-12基因特征进行转录组学比较。该提案的结果解决了IL-12可能在AA中发挥的关键作用，并可能鉴定人AA样本中Th相关的特征异质性。这个指导奖将提供过渡到一个独立的位置的培训框架。他的导师将是国际公认的皮肤和毛发生物学家兼翻译科学家Angela Christiano博士和系统生物学著名专家Andrea Califano博士，他们的兴趣在于组装和询问基因调控模型，以阐明细胞生理学及其疾病失调的机制。Yong-Guang Yang博士是人源化小鼠核心实验室的主任，也是一个专注于移植和急性移植物抗宿主病的实验室的负责人，他还将担任Jabbari博士培训计划的顾问。本文所述的全面培训计划对于Jabbari博士向独立科学家的转变以及他申请学术皮肤病学职业的定位至关重要。

 DESCRIPTION (provided by applicant): This K08 proposal details a comprehensive five-year plan for Dr. Ali Jabbari's career development in basic and translational research in Dermatology. Dr. Jabbari is an early career physician scientist in the Department of Dermatology at Columbia University. Dr. Jabbari's prior clinical and research experience has him uniquely positioned to study alopecia areata (AA), an autoimmune disease in which the hair follicle is the target of attack. Despite its high prevalence, there are no evidence-based treatments for AA. Studies in a C3H/HeJ AA mouse model have shown that the development of AA is critically dependent on the T-helper 1 (Th1)-associated cytokine interferon-γ, and an initial microarray-based assessment of gene expression signatures in the skin of a limited number of human subjects with AA identified the presence of a prominent interferon signature. Dr. Jabbari's proposal addresses the role of IL-12, a prototypical Th1 cytokine, in the pathogenesis of AA. Additionally, he will compare the transcriptional profile of AA, generated from dozens of samples collected through the National Alopecia Areata Registry, to publically available profiles from archetypal Th-associated inflammatory skin diseases. In this proposal, Dr. Jabbari proposes to (i) assess the role of IL-12 in AA development using genetic models of AA, (ii) assess the use of anti-IL- 12 or anti-IL-12R antibodies for therapeutic purposes in AA, and (iii) conduct transcriptomic comparisons of human AA with prototypical Th-associated skin diseases and an IL-12 gene signature. Results from this proposal address the pivotal role IL-12 may be playing in AA and may identify Th-associated signature heterogeneity among human AA samples. This mentored award will provide the training framework for transitioning into an independent position. His mentors will be Dr. Angela Christiano, an internationally-recognized skin and hair biologist and translational scientist, and Dr. Andrea Califano, a renowned expert in systems biology whose interests reside in the assembly and interrogation of gene regulatory models for the elucidation of mechanisms presiding over cell physiology and their dysregulation in disease. Dr. Yong-Guang Yang, Director of the Humanized Mouse Core Facility and head of a laboratory that focuses on transplantation and acute graft versus host disease, will also serve as an advisor for Dr. Jabbari's training plan. The comprehensive training plan described within is critical for Dr. Jabbari's transition to an independent scientist and to position him for applying for a career in academic dermatology.