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: 10259876
• 负责人: Nicole Leanne Ward
• 金额: $ 33.14万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259876
• 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 repurposing; drug testing; efficacy evaluation; 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 derived xenograft model; 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 银屑病研究翻译中心 (CORT) 的总体目标是将新的 生物信息方法与先进的小鼠和人类实验方法转化科学 临床应用的发现可以更灵活地推进牛皮癣和相关炎症的治疗 合并症。我们高度创新、协同和跨学科的 CORT 将采用协作研究 项目（CRP）作为一个中心枢纽，具有来自两个高度互动的研究核心的双向输入，以完善和 测试假设，识别和测试重新利用的药物先导物，并增进对牛皮癣及相关疾病的了解 炎症合并症。为此，CRP 将整合来自以下方面的输入： 1) 临床前建模核心 (PMC)，将提供和定制我们许多经过验证的、独特的转基因银屑病动物模型和 可转化的人类异种移植方法，对于转化新的介质/通路作用和药物先导化合物至关重要； 2）应用元组学核心（AMC），它将应用多平台（转录组、代谢组、 微生物/真菌组）生物信息学对个体患者和小鼠样本进行识别，以识别新的途径特异性 目标。对这些目标的迭代实验测试以及 PMC 和 CRP 的反馈将确定新的目标 银屑病发病机制中的途径可能受益于新的或重新利用的药物的干预 将转化为牛皮癣治疗。我们的首要假设是，我们可以将现有的和 开发牛皮癣基础科学数据集、患者记录、生物信息学和计算系统 通过双向小鼠和人体研究来确定新的治疗靶点和重新利用药物的生物学 可以迅速转移到临床试验，改善牛皮癣的治疗和患者护理。测试和 完善这一假设，具体目标是：(1) 确定银屑病发病机制的新途径和 通过分析银屑病患者的 EMR 数据、组织和血液样本，开发新的银屑病候选药物； (2) 使用临床前评估 AMC 确定的基因靶标和途径特异性候选药物的功效 分子遗传牛皮癣小鼠模型。 CRP 和核心之间的集中相互作用将 提供增值研究成果，远远超出给定核心或特定核心的任何增量进展 项目可以提供。我们新颖、高度集成和协同的 CORT 设计，由卓越的技术提供支持 我们跨学科转化研究团队的资源和专业知识，将发挥变革性和 对银屑病领域和患者护理产生可持续影响。