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

利用皮肤转录和骨髓细胞特征来了解幼年皮肌炎的治疗反应

基本信息

批准号：
10662089
负责人：
Jessica Leigh Turnier
金额：
$ 17.28万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-02 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662089
关键词：
Adhesives Affect Autoimmune Diseases Automobile Driving Bioinformatics Biological Markers Biology Biopsy Blood Blood specimen Calcinosis Caring Cells Cellular biology Child Childhood Chronic Chronic Disease Clinical Cutaneous Data Dermal Dermatologic Development Diagnosis Disease Enrollment Exanthema Flare Functional disorder Funding Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Heterogeneity Idiopathic Inflammatory Myopathies Immune Immune system Immunology Inflammation Inflammation Mediators Inflammatory Investigation Juvenile Dermatomyositis Knowledge Life Longitudinal cohort Lung diseases Macrophage Mediator Mentors Methodology Methods Michigan Modeling Molecular Molecular Analysis Molecular Disease Molecular Target Monitor Muscle Muscle Weakness Myelogenous Myeloid Cells Myopathy Myositis Organ Outcome Pathologic Pathology Pathway interactions Patient Care Patients Pattern Peripheral Blood Mononuclear Cell Phenotype Physicians Population Prognostic Marker Prospective cohort Proteins RNA Refractory Research Research Design Research Personnel Residual state Resolution Role Sampling Scientist Signal Transduction Skin Symptoms Systemic disease Systems Biology Techniques Therapeutic immunosuppression Tissues Training Translational Research Treatment Side Effects Universities Writing biobank biomarker development career career development cohort improved individual patient insight intercellular communication keratinocyte non-invasive monitor novel novel marker oral communication patient oriented peripheral blood precision medicine professor response response biomarker rheumatologist single-cell RNA sequencing skills skin disorder support tools systemic inflammatory response targeted treatment therapeutic target transcriptome transcriptome sequencing transcriptomics treatment response

项目摘要

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.

项目摘要/摘要青少年皮肌炎（JDM）是一种潜在的威胁生命的儿科自身免疫性疾病首先出现皮肤炎症，并可以发展为使肌肉无力，钙化和严重的肺部疾病。三分之二的儿童对初始治疗没有反应，并且缺乏预后生物标志物和靶向治疗。因此，迫切需要更好地理解细胞疾病机制和分子异质性，以促进精确医学。更深入的研究在组织水平上的分子疾病特征，活动炎症经常持续存在潜力描绘出新的疾病机制，生物标志物和治疗靶标。具体的科学目的该项目的时间为1）使用皮肤和周围血液基因表达特征来确定生物学以及JDM治疗反应的预测指标和2）确定单细胞和空间转录表型与治疗难治性JDM有关的皮肤和血液中的髓样细胞的。通过纵向在良好的JDM队列中，方法和非侵入性皮肤采样方法，候选人将表征与治疗有关回复。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。治疗难治性JDM患者的皮肤髓样细胞群另外将在单细胞水平和空间分辨率的单细胞水平上进行评估，以更好地了解髓样细胞作为皮肤炎症和皮肤化系统性免疫串扰的介体。申请人是密歇根大学的助理教授兼儿科流变学家，并积极对待儿童与JDM。她的长期职业目标是提高人们对疾病机制的了解，确定新颖的生物标志物并发现JDM中的治疗靶标，以改善患者的护理。成为独立医师科学家在小儿自身免疫性疾病的分子和细胞机制方面具有专业知识，候选人将实现以下科学培训目标：1）获得与其他患者合作的专业知识生物样本和原代细胞，特别使用角质形成细胞和髓样细胞作为研究免疫的模型 JDM中的失调，2）发展生物信息，单细胞和系统生物学的技能小儿自身免疫性疾病研究的方法，3）在研究设计，整合和分子和临床面向患者数据的分析。候选人还将完成以下职业发展目标：1）发展技能以领导转化研究团队和导师学员，2）改进书面和口头沟通技巧以及3）建立多中心研究网络。申请人形成了参与指导者和顾问团队具有角质形成生物学，免疫学，生物信息学专业知识，单细胞方法和系统生物学方法是集成患者的数据，以指导她拟议的研究和职业发展目标。