Harnessing single cell RNA sequencing and integrative bioinformatics to identify precision therapeutics for dermatomyositis

利用单细胞 RNA 测序和综合生物信息学确定皮肌炎的精准治疗方法

基本信息

批准号：
10573015
负责人：
Jessica Neely
金额：
$ 17.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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/10573015
关键词：
Adrenal Cortex Hormones Adult Advisory Committees Affect Aftercare Animal Model Antigen-Antibody Complex Area Autoantibodies Autoimmune Diseases Award B-Lymphocytes Bioinformatics Biological Assay CD14 gene CD28 gene CD3 Antigens CD8B1 gene California Caring Cell Culture Techniques Cells Child Child Care Childhood Clinical Trials Combined Modality Therapy Complex Cytometry Data Dedications Dermatomyositis Development Plans Disease Disease Outcome Dose Environment FCGR3B gene Faculty Genetic Goals Health Human Immune Immune response Immunologist Immunology Institution Interferon Type I Juvenile Dermatomyositis Knowledge Label Macrophage Maps Measures Mediating Memory B-Lymphocyte Mentors Mentorship Methods Modernization Molecular Morbidity - disease rate Muscle Natural Killer Cells Outcome PTPRC gene Pathogenesis Pathway Analysis Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Physicians Population Positioning Attribute Precision therapeutics Publications Rare Diseases Refractory Regulatory T-Lymphocyte Research Rheumatism Rheumatology San Francisco Scientist Skin Steroids Systems Biology Testing Therapeutic Therapeutic Effect Time Tissues Training Translational Research Universities Work career career development cell type clinical remission cost drug development drug repurposing efficacious treatment experience functional disability immune activation immunopathology improved interest molecular sequence database monocyte mortality novel peripheral blood personalized care pre-clinical precision medicine response rheumatologist single cell analysis single-cell RNA sequencing skills skin disorder targeted treatment therapeutic development transcriptome sequencing transcriptomics translational immunology translational scientist

项目摘要

Project Abstract Dermatomyositis (DM) is a complex immune-mediated systemic condition affecting children and adults for which there are few approved treatments. The mainstay of treatment includes high-dose corticosteroids, which are associated with long-term steroid-related damage. While mortality has improved since the introduction of corticosteroids, over 60% of children and 80% of adults with DM, still experience long-term functional impairment, highlighting the need for improved therapies. Refractory skin disease is especially difficult to treat with only ~1/3 of patients attaining clinical remission. However, DM-specific therapeutic development has been hindered because of the rarity of the disease, few preclinical animal models, and the time and cost associated with traditional drug development pipelines. To circumvent these barriers and identify precision medicine treatments for DM, we propose a novel computational drug repositioning strategy to identify existing compounds that target perturbed molecular networks in DM-associated cell types using a combination of single-cell network analyses, transcriptomic-based computational drug repurposing, and ex-vivo cell culture assays in PBMCs and skin. In Specific Aim 1, we will identify the cell-specific immune pathways dysregulated in juvenile DM PBMCs and DM skin compared to healthy controls using single-cell RNA sequencing. In Specific Aim 2, we will apply transcriptomic-based computational drug repurposing to identify single agent and combination therapies that target cell-specific immune signatures in peripheral blood and skin. In Specific Aim 3, we will determine the effects of predicted single agent and combination therapies on immune cell activation using ex-vivo PBMC and skin culture assays. We expect the summary of this work to advance knowledge of DM pathogenesis at the cellular level and to rapidly identify compounds that can be repurposed for the treatment of DM with the long-term goal of improving disease outcomes. The candidate’s career goal is to become a translational researcher and computational immunologist investigating the immune dysregulation of rheumatic diseases to inform precision medicine approaches to care. In this K08 proposal, the candidate has developed a career development plan, which requests training in advanced single cell analysis methods, computational drug repurposing, and translational immunology to gain the skills needed to achieve this goal. The candidate is trained in Pediatric Rheumatology and holds a faculty position at the University of California, San Francisco. The candidate has assembled a mentorship and advisory team with expertise in integrative bioinformatics, basic immunology, skin immunology, systems biology, translational research, and clinical trials. The scientific environment at this institution, superb mentorship and advisory team supporting the candidate, and proposed research aims will enable the candidate’s transition to an independent career as a physician scientist dedicated to developing precision medicine approaches to care for people with rare rheumatic conditions.

项目摘要皮肌炎 (DM) 是一种复杂的免疫介导的系统性疾病，影响儿童和成人批准的治疗方法很少。主要治疗方法包括大剂量皮质类固醇。与长期类固醇相关的损害有关，而自引入以来死亡率有所改善。皮质类固醇治疗后，超过 60% 的儿童和 80% 的糖尿病成人患者仍存在长期功能障碍损害，强调需要改进的治疗方法。难治性皮肤病尤其难以治疗。尽管只有约 1/3 的患者获得临床缓解，但针对 DM 的治疗方法已得到开发。由于该疾病的罕见性、临床前动物模型很少以及相关的时间和成本而受到阻碍与传统的药物开发管道一起规避这些障碍并确定精准医学。针对 DM 的治疗，我们提出了一种新的计算药物重新定位策略来识别现有的使用以下组合靶向 DM 相关细胞类型中扰动分子网络的化合物单细胞网络分析、基于转录组学的计算药物再利用和离体细胞培养在特定目标 1 中，我们将识别失调的细胞特异性免疫途径。使用单细胞 RNA 测序将青少年 DM PBMC 和 DM 皮肤与健康对照进行比较。在具体目标 2 中，我们将应用基于转录组学的计算药物再利用来识别单一药物以及针对外周血和皮肤中细胞特异性免疫特征的联合疗法。在具体目标 3 中，我们将确定预测的单药和联合疗法对使用离体 PBMC 和皮肤培养测定法激活免疫细胞。我们期望这项工作的总结能够在细胞水平上增进对 DM 发病机制的了解，并快速识别可重新用于治疗 DM 的化合物，长期目标是改善候选人的职业目标是成为一名转化研究员和计算研究员。免疫学家研究风湿性疾病的免疫失调，为精准医学提供信息在此 K08 提案中，候选人制定了职业发展计划。要求接受高级单细胞分析方法、计算药物再利用和转化方面的培训免疫学以获得实现这一目标所需的技能候选人接受过儿科风湿病学培训。并在加州大学旧金山分校担任教职。具有综合生物信息学、基础免疫学、皮肤免疫学专业知识的指导和咨询团队，该机构的科学环境非常好，包括系统生物学、转化研究和临床试验。支持候选人的导师和咨询团队以及拟议的研究目标将使候选人过渡到作为一名致力于提高精度的医师科学家的独立职业治疗罕见风湿病患者的医学方法。