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

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

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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状况，影响儿童和成人几乎没有批准的治疗方法。治疗的主要手段包括高剂量皮质类固醇，与长期类固醇相关的损伤有关。自从引入以来，死亡率有所提高皮质类固醇，超过60％的儿童和80％的DM成年人，仍然具有长期功能损害，强调需要改善疗法的需求。难治性皮肤疾病特别难以治疗只有〜1/3的患者达到临床缓解。但是，DM特异性的治疗性开发已经由于疾病的稀有性，几乎没有临床前动物模型以及与时间和成本相关的因素而受到阻碍使用传统的药物开发管道。绕过这些障碍并确定精确医学 DM的治疗方法，我们提出了一种新型的计算药物重新定位策略，以识别现有靶向与DM相关细胞类型中分子网络的靶向的化合物，结合了单细胞网络分析，基于转录组的计算药物重新定位和前体细胞培养 PBMC和皮肤的测定。在特定目标1中，我们将确定细胞特异性免疫途径失调与使用单细胞RNA测序的健康对照组相比，在少年DM PBMC和DM皮肤中。在特定的目标2中，我们将应用基于转录组的计算药物重新使用以识别单个药物以及靶向外周血和皮肤中细胞特异性免疫特异性特异性免疫特征的组合疗法。在特定的目标3中，我们将确定预测的单药和组合疗法对免疫细胞使用EX-VIVO PBMC和皮肤培养测定法。我们期望这项工作的摘要能够提高细胞水平上DM发病机理的了解和迅速识别可以重新用于治疗DM的化合物，其长期目标是改善疾病结果。候选人的职业目标是成为翻译研究人员和计算免疫学家研究风湿病的免疫失调以告知精确医学护理方法。在这个K08提案中，候选人制定了一项职业发展计划，该计划要求进行高级单细胞分析方法，计算药物重新利润和翻译培训免疫学以获得实现这一目标所需的技能。候选人接受了儿科风湿病学培训并在加利福尼亚大学旧金山担任教职员工。候选人组装了具有综合生物信息学，基本免疫学，皮肤免疫学的遗产和咨询团队，系统生物学，翻译研究和临床试验。该机构的科学环境很棒支持候选人的Menorship和咨询团队，拟议的研究目标将使候选人过渡到独立职业，作为一名致力于发展精度的物理科学家医学方法来照顾罕见的风湿病患者。