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

• 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
• 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

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全身性疾病，影响儿童和成人 几乎没有得到批准的治疗方法。治疗的主要手段包括大剂量的皮质类固醇， 与长期的类固醇相关损害有关。虽然死亡率自引入以来有所改善 糖皮质激素，超过60%的儿童和80%的糖尿病成人患者，仍然经历着长期的功能性 损害，突出了改进治疗的必要性。难治性皮肤病尤其难治 仅有1/3的患者获得临床缓解。然而，针对糖尿病的治疗发展一直是 由于疾病的罕见，临床前动物模型很少，以及相关的时间和成本，这一点受到了阻碍 与传统的药物开发管道合作。绕过这些障碍，识别精准医学 对于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 以DM相关细胞类型中受扰动的分子网络为靶点的化合物 单细胞网络分析、基于转录的计算药物再利用和体外细胞培养 外周血单核细胞和皮肤中的检测。在特定的目标1中，我们将识别细胞特异性免疫通路失调。 采用单细胞RNA测序技术对青少年糖尿病患者PBMCs和糖尿病皮肤患者与健康对照组进行比较。 在具体目标2中，我们将应用基于转录的计算药物再利用来鉴定单一药物。 以及针对外周血液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一药物和联合治疗对 免疫细胞激活使用体外PBMC和皮肤培养试验。 我们期望这项工作的总结将在细胞水平上促进对DM发病机制的了解，并 快速确定可用于治疗糖尿病的化合物，长期目标是改善 疾病后果。应聘者的职业目标是成为一名翻译研究员和计算专家 免疫学家研究风湿病免疫失调为精准医学提供信息 护理的方法。在这份K08提案中，候选人制定了职业发展计划，其中 要求接受高级单细胞分析方法、计算药物再利用和翻译方面的培训 以获得实现这一目标所需的技能。应聘者受过儿科风湿病方面的培训 并在加州大学旧金山分校担任教职。这位候选人已经召集了一位 具有综合生物信息学、基础免疫学、皮肤免疫学、 系统生物学、转化研究和临床试验。这个机构的科学环境，一流的 支持候选人的导师和顾问团队，以及拟议的研究目标将使 候选人过渡到独立的职业生涯，成为一名致力于开发精度的内科科学家 治疗罕见风湿病的医学方法。