Project 1: Host Immune Response to Chronic Psoriasis Inflammation

项目 1：宿主对慢性银屑病炎症的免疫反应

• 批准号: 10005125
• 负责人: Nicole Leanne Ward
• 金额: $ 33.34万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005125
• 关键词: Advisory Committees; Animal Model; Artificial Intelligence; Basic Science; Bioinformatics; Blood; Blood specimen; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Critical Pathways; Custom; Data; Data Set; Databases; Decision Making; Development; Disease; Drug Targeting; Feedback; Gene Targeting; Genes; Genetic; Goals; Growth; Healthcare; Human; Human Resources; Immune response; Inflammation; Inflammatory; Intervention; Intervention Studies; Lead; Leadership; Machine Learning; Mediator of activation protein; Medical; Methodology; Methods; Modeling; Molecular Genetics; Mus; Ohio; Output; Pathogenesis; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Pilot Projects; Pre-Clinical Model; Provider; Psoriasis; Psoriatic Arthritis; Records; Research; Research Project Grants; Resource Allocation; Resources; Role; Sampling; Skin; System; Systems Biology; Testing; Therapeutic; Tissue Sample; Transgenic Organisms; Translating; Translational Research; Xenograft procedure; base; clinical application; cohesion; comorbidity; data mining; design; drug candidate; drug discovery; drug testing; improved; in silico; in vitro Bioassay; individual patient; inflammatory marker; innovation; insight; meetings; metabolome; microbiome; mouse model; mycobiome; new therapeutic target; novel; novel therapeutics; patient oriented; patient stratification; personalized medicine; personalized predictions; post intervention; pre-clinical; pre-clinical research; programs; repository; synergism; therapy design; transcriptome; translational approach

The overall goal of the CWRU Psoriasis Center of Research Translation (CORT) is to combine new bioinformatic methodologies with advanced murine and human experimental approaches to translate scientific findings into clinical applications that more nimbly advance therapy for psoriasis and related inflammatory comorbidities. Our highly innovative, synergistic and cross-disciplinary CORT will use a collaborative research project (CRP) as a central hub with bi-directional input from 2 highly interactive research cores, to refine and test hypotheses, identify and test repurposed drug leads and advance understanding of psoriasis and related inflammatory comorbidities. To do so, the CRP will integrate input from the: 1) Preclinical Modeling Core (PMC), that will provide and customize our many validated, unique transgenic psoriasiform animal models and translatable human xenograft approaches, essential to translating new mediator/pathway roles and drug leads; and the 2) Applied Meta-‘Omics Core (AMC), that will apply multi-platform (transcriptome, metabolome, micro/mycobiome) bioinformatics to individual patient and murine samples to identify novel pathway-specific targets. Iterative experimental testing of these targets and feedback from the PMC and CRP will identify novel pathways in psoriasis pathogenesis that are likely to benefit from intervention by new or repurposed drugs that will translate to psoriasis therapy. Our overarching hypothesis is that we can powerfully combine existing and developing psoriasis basic science datasets, patient records, bioinformatics and computational systems biology with bi-directional mouse and human studies to identify new therapeutic targets and repurposed drugs that can be expeditiously moved to clinical trials, improving psoriasis treatment and patient care. To test and refine this hypothesis, the Specific Aims are: (1) Identify new pathways central to psoriasis pathogenesis and new psoriasis drug candidates by analyzing psoriasis patients' EMR data, tissue and blood samples and; (2) Evaluate AMC-identified gene targets and efficacy of pathway-specific drug candidates using preclinical molecular genetic psoriasis mouse models. The concentrated interactions between the CRP and Cores will provide value-added research output, far beyond any incremental advances that a given Core or specific project could provide. Our novel, highly integrated and synergistic CORT design, powered by exceptional resources and expertise of our interdisciplinary translational investigative team, will exert a transformative and sustainable impact on the psoriasis field and patient care.

CWRU翻译研究中心（CORT）的总体目标是将联合收割机 生物信息学方法与先进的小鼠和人类实验方法， 临床应用的发现，更灵活地推进治疗银屑病和相关炎症 合并症。我们高度创新，协同和跨学科的CORT将使用合作研究 项目（CRP）作为一个中心枢纽，来自2个高度互动的研究核心的双向输入， 测试假设，识别和测试重新使用的药物线索，并促进对银屑病及相关疾病的了解 炎性合并症。为此，CRP将整合来自以下方面的输入：1）临床前建模核心 (PMC)，这将提供和定制我们许多经过验证的，独特的转基因银屑病样动物模型， 可翻译的人类异种移植方法，对于翻译新的介质/通路作用和药物先导物至关重要; 以及2）应用Meta-组学核心（AMC），其将应用多平台（转录组，代谢组， 微生物/真菌生物群系）生物信息学，以鉴定新的途径特异性 目标的这些目标的迭代实验测试以及PMC和CRP的反馈将确定新的 银屑病发病机制中可能受益于新的或重新用途的药物干预的途径， 将转化为牛皮癣治疗。我们的首要假设是，我们可以将现有的联合收割机和 开发银屑病基础科学数据集、患者记录、生物信息学和计算系统 生物学与双向小鼠和人类研究，以确定新的治疗靶点和重新利用的药物 可以迅速进入临床试验，改善银屑病治疗和患者护理。测试和 完善这一假设，具体的目的是：（1）确定新的途径，中央银屑病发病机制， 通过分析银屑病患者的EMR数据、组织和血液样本，获得新的银屑病候选药物;（2） 使用临床前试验评估AMC确定的基因靶点和途径特异性候选药物的疗效 分子遗传银屑病小鼠模型。CRP和核心之间的集中相互作用将 提供增值的研究成果，远远超过任何增量的进步，一个给定的核心或特定的 项目可以提供。我们新颖、高度集成和协同的CORT设计， 我们的跨学科翻译调查团队的资源和专业知识，将发挥变革性和 持续影响牛皮癣领域和患者护理。