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

项目总结/摘要 幼年型皮肌炎（JDM）是一种可能危及生命的儿科自身免疫性疾病， 首先表现为皮肤炎症，并可进展为使人衰弱的肌肉无力、钙质沉着， 严重的肺部疾病三分之二的儿童对初始治疗没有反应，并且缺乏预后评估。 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，以推进精准医疗。深入调查 组织水平的分子疾病特征（活动性炎症经常持续存在）占据了主导地位， 描述新的疾病机制、生物标志物和治疗靶点的潜力。具体的科学目标 本项目的主要目的是：1）利用皮肤和外周血基因表达特征来确定生物学 和JDM治疗反应的预测因子，以及2）确定单细胞和空间转录表型 与难治性JDM相关的皮肤和血液中的骨髓细胞。通过纵向 方法和非侵入性皮肤采样方法在一个良好的表型JDM队列，候选人将 表征与治疗相关的病变和非病变皮肤中的皮肤转录组特征 反应候选人将利用配对的血液样本直接比较组织特异性的重要性。 生物标志物开发中的签名。难治性JDM患者的皮肤髓系细胞群 此外，还将在单细胞水平上以空间分辨率进行评估，以更好地了解 骨髓细胞作为皮肤炎症和皮肤-全身免疫串扰的介质。申请人 他是密歇根大学的助理教授和儿科风湿病学家， 关于JDM她的长期职业目标是推进疾病机制的知识，识别新的生物标志物， 并发现JDM的治疗靶点，以改善对患者的护理。成为一个独立 儿科自身免疫性疾病的分子和细胞机制方面的专业医生科学家， 候选人将完成以下科学培训目标：1）获得与其他患者合作的专业知识 生物样品和原代细胞，特别是使用角质形成细胞和骨髓细胞，作为研究免疫的模型， JDM中的失调，2）发展生物信息学，单细胞和系统生物学应用的技能 儿童自身免疫性疾病研究的方法，以及3）获得研究设计，整合和 分析分子和临床患者导向的数据。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 3）建立多中心的科研网络。申请人已成立一个 在角质形成细胞生物学、免疫学、生物信息学， 单细胞方法和系统生物学方法来整合面向患者的数据，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.