Defining T helper cell associated cytokines and mechanisms in Alopecia Areata

斑秃中 T 辅助细胞相关细胞因子和机制的定义

基本信息

批准号：
9979751
负责人：
Ali Jabbari
金额：
$ 17.09万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979751
关键词：
Acute Acute Graft Versus Host Disease Address Affect Allergic rhinitis Alopecia Areata Antibodies Area Asthma Atopic Dermatitis Autoimmune Diseases Award Basic Science Bone Marrow Bone Marrow Cells C57BL/6 Mouse Case Series Cell physiology Chimera organism Clinical Research Clinical Trials Contact Dermatitis Core Facility Data Databases Deposition Dermatology Development Disease Disease remission Effector Cell Evidence based treatment Exhibits Five-Year Plans Gene Expression Gene Expression Profile Genetic Models Genetic Transcription Hair Hair follicle structure Head Helper-Inducer T-Lymphocyte Heterogeneity High Prevalence Human Immunotherapy Inbreeding Individual Inflammatory Institution Interferons Interleukin-12 Interleukin-12 Gene International Laboratories Lupus Mediating Mentors Microarray Analysis Modeling Molecular Molecular Profiling Mus Pathogenesis Pathogenicity Pathology Pathway interactions Patients Pharmacology Physicians Play Positioning Attribute Prevention Process Psoriasis Receptor Signaling Recording of previous events Regulator Genes Reporting Resolution Role Sampling Scientist Signal Transduction Skin Skin graft Stimulus Systems Biology T-Cell Receptor T-Lymphocyte Th2 Cells Therapeutic Therapeutic antibodies Training Translational Research Transplantation United States Universities Yang alopecia areata registry atopy autoreactive T cell base career career development cytokine design experience genetic signature human subject humanized mouse improved individualized medicine inhibitor/antagonist interest interleukin-12 receptor lupus cutaneous molecular phenotype mouse model new therapeutic target prevent public health relevance response risk benefit ratio skin disorder small molecule targeted agent tool transcriptomics translational scientist treatment strategy

项目摘要

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.

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) 方面具有独特的优势，斑秃是一种自身免疫性疾病，尽管发病率很高，但毛囊却是其攻击目标。 C3H/HeJ AA 小鼠模型的研究表明，AA 的发生严重依赖于 T 辅助细胞 1 (Th1) 相关的细胞因子干扰素-γ，并且初始的 AA 治疗方法尚无证据。对有限数量的 AA 人类受试者皮肤中的基因表达特征进行基于微阵列的评估，发现存在显着的干扰素特征。Jabbari 博士的提议涉及 IL-12（一种典型的干扰素）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 转录谱与典型 Th 相关炎症性皮肤病的公开谱进行比较。 Jabbari 博士建议 (i) 使用 AA 遗传模型评估 IL-12 在 AA 发育中的作用，(ii) 评估抗 IL-12 或抗 IL-12R 抗体的使用用于 AA 的治疗目的，(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，并可能确定。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头发生物学家和转化科学家安吉拉·克里斯蒂安诺 (Angela Christiano) 博士。 Andrea Califano 博士是一位著名的系统生物学专家，他的兴趣在于基因调控模型的组装和研究，以阐明细胞生理学及其在疾病中的失调的机制。Yong-Guang Yang 博士是人源化小鼠的主任。核心设施和专注于移植和急性移植物抗宿主病的实验室负责人也将担任贾巴里博士培训计划的顾问。贾巴里转变为一名独立科学家，并为他申请学术皮肤病学职业奠定了基础。