Defining T helper cell associated cytokines and mechanisms in Alopecia Areata

 描述（由申请人提供）：本 K08 提案详细介绍了 Ali Jabbari 博士在皮肤病学基础和转化研究领域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一名早期职业医师科学家。 Jabbari 博士之​​前的临床和研究经验使他在研究斑秃 (AA) 方面拥有独特的优势，斑秃是一种以毛囊为攻击目标的自身免疫性疾病。尽管 AA 患病率很高，但尚无基于证据的治疗方法。 C3H/HeJ AA 小鼠模型的研究表明，AA 的发展严重依赖于 T 辅助细胞 1 (Th1) 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进行了基于微阵列的初步评估，发现了显着的干扰素特征的存在。 Jabbari 博士的提案阐述了 IL-12（一种典型的 Th1 细胞因子）在 AA 发病机制中的作用。此外，他还将通过国家斑秃登记处收集的数十个样本生成的 AA 转录谱与公开的典型 Th 相关炎症性皮肤病的转录谱进行比较。在该提案中，Jabbari 博士建议 (i) 使用 AA 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-12R 抗体在 AA 治疗中的使用，以及 (iii) 对人类 AA 与典型 Th 相关皮肤病和 IL-12 基因特征进行转录组比较。该提案的结果说明了 IL-12 在 AA 中可能发挥的关键作用，并且可以识别人类 AA 样本中与 Th 相关的特征异质性。该指导奖项将为过渡到独立职位提供培训框架。他的导师将是国际公认的皮肤和毛发生物学家和转化科学家 Angela Christiano 博士和系统生物学著名专家 Andrea Califano 博士，后者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在疾病中的失调的机制。人源化小鼠核心设施主任兼移植和急性移植物抗宿主病实验室负责人杨永光博士也将担任贾巴里博士培训计划的顾问。其中描述的全面培训计划对于贾巴里博士过渡为独立科学家并帮助他申请学术皮肤病学职业至关重要。

 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.