Core 1: Pre-clinical Modeling Core

核心 1：临床前建模核心

基本信息

批准号：
10259874
负责人：
Nicole Leanne Ward
金额：
$ 31.41万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10259874
关键词：
Acute Animal Model Animals Back Big Data Bioinformatics Biological Markers Biological Models Blood Blood Cells Bone Marrow Transplantation Cells Clinical Core Facility Data Data Analyses Engineering Future Gene Proteins Generations Genetic Germ-Free Gnotobiotic Goals Human Imiquimod Immune response In Vitro Inflammation Inflammatory Knock-out Knockout Mice Link Mediating Mediator of activation protein Methodology Modeling Modification Molecular Molecular Genetics Mouse Strains Mus Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Preclinical Testing Psoriasis Research Research Project Grants Resources Role Sampling Skin Structure System Technology Testing Tissues Transgenic Organisms Translating Translational Research Transplantation Validation Xenograft procedure bacteriome base clinical application clinical care clinical translation cohort comorbidity drug repurposing drug testing efficacy testing experimental study flexibility genetic approach genetic manipulation in vivo innovation insight interleukin-17C interleukin-23 meetings metabolomics microbial mouse model mycobiome novel pre-clinical preclinical evaluation reconstitution skin lesion skin xenograft success tool transcriptomics treatment response

项目摘要

The CORT Preclinical Modeling Core (PMC) will serve as a resource for the Collaborative Research Project (CRP), providing enabling technology and model systems that will be used to specifically test targets identified by the Applied Meta-Omics Core (AMC). The broad goal of the CWRU 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. This goal requires a rich array of readily-deployable and flexible/adaptable psoriasis-relevant and innovative in vivo systems that permit testing of a wide range of novel concepts, roles of specific mediator/pathways, and efficacies of specific repurposed and anti-psoriasis drugs. The PMC will meet this need, by working closely with the AMC and CRP to provide all needed transgenic and psoriasiform mouse models and isolated tissues, blood and cells for analyses and bioinformatic-derived biomarker and target generation. The PMC will enable generation and testing by the CRP of hypotheses generated as a result of human and mouse bioinformatics data. The goals of the PMC include providing enabling materials, technology and expertise in psoriasis mouse models and mouse molecular genetics that will allow and enhance successful completion of the CRP Aims and Objectives. To support the CRP’s objectives, the PMC will: A. Provide genetically modified existing mouse models of psoriasiform skin inflammation; B. Engineer new innovative genetic mouse models based upon novel genes/proteins identified by the AMC; C. Provide primary cells isolated from genetically manipulated mice for ex vivo hypothesis testing; D. Identify the most appropriate psoriasis mouse model(s) to test efficacy of pathway-specific drugs identified by the AMC, and generate and provide mice to the CRP for preclinical testing and evaluation; and E. Generate germ-free mice and re- introduce bacteriome/mycobiome species identified by the AMC and provide animals to the CRP for analysis and hypothesis testing. The PMC will also provide reiterative data generation for additional “omics” data analyses and identification by the AMC of novel pathways, biomarkers, micro/mycobiome species, and cellular mediators, contributing new insight into psoriasis pathogenesis, enabling validation in clinical psoriasis patient samples. The PMC provides a coordinated center of excellence enabling the creation of new, and utilization of existing, animal models of psoriasis to better test the cellular and molecular mechanisms hypothesized to mediate psoriasis. Within the novel CORT structure of highly interactive Cores synergistically interacting with the central CRP, the PMC team's expertise, innovation and extensive resources will drive the CORT's transforming and sustainable impact on psoriasis understanding and clinical care.

CORT 临床前建模核心 (PMC) 将作为协作研究的资源项目（CRP），提供将用于专门测试目标的使能技术和模型系统由应用元组学核心 (AMC) 确定 CWRU CORT 的总体目标是结合新的技术。生物信息方法学与先进的小鼠和人类实验方法进行翻译将科学发现转化为临床应用，更灵活地推进牛皮癣及相关疾病的治疗这一目标需要一系列丰富的易于部署且灵活/适应性强的措施。与银屑病相关的创新体内系统，可以测试各种新概念、作用 PMC 将召开会议，讨论特定介质/途径以及特定用途和抗银屑病药物的功效。为了满足这一需求，我们与 AMC 和 CRP 密切合作，提供所有需要的转基因小鼠和银屑病小鼠模型和分离的组织、血液和细胞，用于分析和生物信息衍生的生物标志物和靶标 PMC 将使 CRP 能够生成和测试由于生成而产生的假设。 PMC 的目标包括提供人类和小鼠生物信息学数据。以及银屑病小鼠模型和小鼠分子遗传学方面的专业知识，这将允许并增强成功完成 CRP 的目的和目标为了支持 CRP 的目标，PMC 将： A. 提供 B. 改造现有的银屑病皮肤炎症小鼠模型；基于 AMC 鉴定的新基因/蛋白质的遗传小鼠模型 C. 提供原代细胞；从基因操作小鼠中分离出来进行离体假设检验；D. 确定最合适的银屑病小鼠模型，用于测试 AMC 确定的途径特异性药物的功效，并生成和向 CRP 提供小鼠进行临床前测试和评估；以及 E. 生成无菌小鼠并重新制备；引入 AMC 鉴定的细菌组/真菌组物种，并将动物提供给 CRP 进行分析 PMC 还将为额外的“组学”数据提供重复数据生成。 AMC 对新途径、生物标志物、微生物/真菌物种和细胞进行分析和鉴定介质，为银屑病发病机制提供新的见解，从而能够在临床银屑病患者中进行验证 PMC 提供了一个协调的卓越中心，能够创建新的样本并加以利用。现有的牛皮癣动物模型，以更好地测试探索的细胞和分子机制在高度相互作用的核心的新颖 CORT 结构中，与银屑病协同作用。中央 CRP、PMC 团队的专业知识、创新和广泛的资源将推动 CORT 的发展对银屑病认识和临床护理产生变革性和可持续的影响。