Defining T helper cell associated cytokines and mechanisms in Alopecia Areata

 描述(由申请者提供)：这份K08建议书详细介绍了阿里·贾巴里博士在皮肤科基础研究和转化性研究方面的职业发展的综合五年计划。贾巴里博士是哥伦比亚大学皮肤科早期职业内科科学家。Jabbari博士先前的临床和研究经验使他在研究斑秃(AA)方面具有独特的地位，这是一种以毛囊为攻击目标的自身免疫性疾病。尽管再生障碍性贫血的患病率很高，但还没有循证的治疗方法。在C3H/HeJ AA小鼠模型中的研究表明，再生障碍性贫血的发展严重依赖于T辅助1(Th1)相关的细胞因子干扰素-γ，基于微阵列的初步评估发现，少数再生障碍性贫血受试者皮肤中的基因表达特征存在显著的干扰素特征。贾巴里博士的建议解决了IL-12在再生障碍性贫血发病机制中的作用，IL-12是一种典型的Th1细胞因子。此外，他将比较从国家斑秃登记处收集的数十个样本中产生的AA的转录图谱，以及典型的Th相关炎症性皮肤病的公开可用图谱。在这项建议中，Jabbari博士建议(I)使用再生障碍性贫血的遗传模型评估IL-12在再生障碍性贫血发展中的作用，(Ii)评估抗IL-12或抗IL-12R抗体在再生障碍性贫血治疗中的使用，以及(Iii)对人类再生障碍性贫血与典型的Th相关皮肤病和IL-12基因签名进行转录转录比较。这项建议的结果解决了IL-12在再生障碍性贫血中可能扮演的关键角色，并可能识别人类再生障碍性贫血样本中与Th相关的信号异质性。这一指导奖将提供过渡到独立职位的培训框架。他的导师将是国际公认的皮肤和头发生物学家和翻译科学家安吉拉·克里斯蒂亚诺博士，以及著名的系统生物学专家安德里亚·卡利法诺博士，他的兴趣在于组装和询问基因调控模型，以阐明控制细胞生理的机制及其在疾病中的失调。人性化小鼠核心设施主任、专注于移植和急性移植物抗宿主病的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。文章中描述的全面培训计划对于贾巴里博士向独立科学家的转变以及为申请皮肤科学术生涯做好准备至关重要。

 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.