Harnessing cutaneous transcriptional and myeloid cell signatures to understand treatment response in juvenile dermatomyositis

项目摘要/摘要 青少年皮肌炎(JDM)是一种潜在威胁生命的儿科自身免疫性疾病，经常 首先表现为皮肤炎，可进展为衰弱的肌肉无力、钙质沉着和 严重的肺部疾病。三分之二的儿童对最初的治疗没有反应，缺乏预后。 生物标志物和靶向治疗。因此，迫切需要更好地了解细胞 疾病机制和分子异质性，以推进精准医学。更深入地调查 在组织水平上的分子疾病特征，其中活动性炎症经常持续，持有 描述新的疾病机制、生物标记物和治疗目标的可能性。具体的科学目标 这个项目的目的是1)利用皮肤和外周血液的基因表达特征来确定生物学 和JDM治疗反应的预测因素以及2)确定单细胞和空间转录表型 皮肤和血液中的髓系细胞与治疗难治性JDM有关。通过纵向的 在一个表型良好的JDM队列中，候选人将 皮损和非皮损皮肤中与治疗相关的皮肤转录特征 回应。候选人将利用配对的血液样本直接比较特定组织的重要性 生物标记物开发中的签名。皮肤髓系细胞在治疗难治性JDM中的作用 将在具有空间分辨率的单细胞水平上进行额外评估，以更好地理解 髓系细胞作为皮肤炎症和皮肤-系统免疫串扰的媒介。申请人是 密歇根大学的助理教授和儿科风湿病专家，积极治疗儿童 和JDM一起。她的长期职业目标是促进疾病机制的知识，识别新的生物标记物 并发现JDM的治疗靶点，以改善对她的患者的护理。成为一名独立人士 在儿科自身免疫性疾病的分子和细胞机制方面拥有专业知识的内科科学家 应聘者将完成以下科学培训目标：1)获得与其他患者打交道的专业知识 生物样本和原代细胞，特别是使用角质形成细胞和髓系细胞作为研究免疫的模型 2)发展生物信息学、单细胞和系统生物学的应用技能 儿童自身免疫性疾病的研究方法，以及3)在研究设计、整合和 以患者为中心的分子和临床数据分析。候选人还将完成以下职业生涯 发展目标：1)培养领导翻译研究团队和指导学员的技能；2)提高书面表达能力 和口语交流技能；3)建立多中心研究网络。申请人已形成一份 拥有角质形成细胞生物学、免疫学、生物信息学专业知识的导师和顾问团队， 单细胞方法和系统生物学方法集成面向患者的数据，以指导她在 提出学习和职业发展目标。

PROJECT SUMMARY/ABSTRACT Juvenile dermatomyositis (JDM) is a potentially life-threatening pediatric autoimmune disease that frequently first presents with cutaneous inflammation and can progress to debilitating muscle weakness, calcinosis, and severe lung disease. Two-thirds of children do not respond to initial treatment, and there is a lack of prognostic biomarkers and targeted treatments. Thus, there is a critical need to develop a better understanding of cellular disease mechanisms and molecular heterogeneity to advance precision medicine. Deeper investigation of molecular disease signatures at the tissue level, where active inflammation frequently persists, holds the potential to delineate novel disease mechanisms, biomarkers and treatment targets. The specific scientific aims of this project are to 1) Utilize cutaneous and peripheral blood gene expression signatures to determine biology and predictors of JDM treatment response and 2) Determine single-cell and spatial transcriptional phenotypes of myeloid cells within skin and blood that are associated with treatment refractory JDM. Through a longitudinal approach and non-invasive skin sampling methodology in a well-phenotyped JDM cohort, the candidate will characterize cutaneous transcriptomic signatures in both lesional and non-lesional skin as related to treatment response. The candidate will leverage paired blood samples to directly compare the importance of tissue-specific signatures in biomarker development. Cutaneous myeloid cell populations in treatment refractory JDM patients will additionally be assessed at a single-cell level with spatial resolution to better understand the potential role of myeloid cells as mediators of cutaneous inflammation and dermal-systemic immune crosstalk. The applicant is an Assistant Professor and Pediatric Rheumatologist at the University of Michigan and actively treats children with JDM. Her long-term career goal is to advance knowledge of disease mechanisms, identify novel biomarkers and discover therapeutic targets in JDM in order to improve care for her patients. To become an independent physician scientist with expertise in molecular and cellular mechanisms of pediatric autoimmune disease, the candidate will accomplish the following scientific training goals: 1) gain expertise in working with additional patient biosamples and primary cells, specifically using keratinocytes and myeloid cells, as a model to study immune dysregulation in JDM, 2) develop skills in the application of bioinformatic, single-cell and systems biology approaches to the study of pediatric autoimmune disease, and 3) gain expertise in study design, integration and analysis of molecular and clinical patient-oriented data. The candidate will also complete the following career development goals: 1) develop skills to lead a translational research team and mentor trainees, 2) improve written and oral communication skills and 3) establish a multicenter research network. The applicant has formed an engaged team of mentors and advisors with expertise in keratinocyte biology, immunology, bioinformatics, single-cell methods and systems biology approaches to integration of patient-oriented data to guide her in the proposed study and career development goals.