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A consortium effort to translate therapies for neurological diseases via an ex vivo organotypic platform

一个联盟致力于通过离体器官平台转化神经系统疾病的疗法

基本信息

批准号：
10436954
负责人：
ALBERT Sidney BALDWIN
金额：
$ 115.03万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436954
关键词：
Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Model Animal Testing Area Biological Assay Biopsy Biopsy Specimen Brain Brain Diseases Brain Neoplasms Brain Pathology Cancer Model Cell Death Cell Therapy Cells Cellular Assay Cellular immunotherapy Chemicals Clinical Clinical Research Collaborations Communities DNA lesion Development Discipline Disease Disease Progression Disease model Drug Screening Effectiveness Florida Foundations Gene Targeting Genes Genomics Glioblastoma Goals Grant Heterogeneity Human Huntington Disease Immune Immunotherapy Individual Infarction Inflammatory Infrastructure Ischemic Stroke Laboratories Malignant Neoplasms Malignant neoplasm of brain Mediating Medical Methods Microglia Modeling Molecular NF-kappa B Neurodegenerative Disorders Neurologic Neurological Models Parkinson Disease Pathway interactions Patient Care Patient-Focused Outcomes Patients Pharmaceutical Preparations Process Program Development Reporter Research Resources Role Series Signal Pathway Signal Transduction Slice Small Interfering RNA Stroke Structure System Techniques Technology Testing Therapeutic Therapeutic Agents Time Tissues Transfection Translating Translations Viral animal efficacy anti-cancer base brain disorder therapy brain tissue chimeric antigen receptor T cells clinical efficacy cost drug development drug discovery efficacy study experience extracellular gene gun gene therapy improved improved outcome inhibitor innovation knock-down member molecular imaging mouse model multidisciplinary nervous system disorder next generation novel novel therapeutics optical imaging prevent programs real time monitoring screening small molecule stem cell therapy technological innovation therapeutically effective tool treatment response tumor heterogeneity

项目摘要

Project Summary/Abstract Disorders of the brain remain an enormous medical challenge. New platforms that allow functional testing in high-fidelity systems that incorporate patient tissue and high-throughput capacity are urgently needed to bridge gap between cell-based assays and whole-animal testing. We propose a multi-institutional effort to identify, develop, and initiate translation of therapeutic neurological agents using the organotypic brain slice culture (OBSC) platform. Our OBSC models leverage existing cellular and extracellular milieu in the live brain slices to allow rapid, functional testing on brain tissue. Our multi-disciplinary team, which spans three CTSA Program hubs (UNC, Duke, and Univ. Florida), has developed multiple models for neurological disorders and shown the effectiveness of the OBSC platform to discover new mechanisms of disease and identify new therapeutic compounds. We have developed technological innovations for OBSC modeling, including elevated-throughput techniques for brain slicing, viral- and biolistic-based transduction of disease-relevant genes, targeted gene knockdown, real-time monitoring using reporter assays, and incorporation of fresh patient tissue. We now seek to leverage the power of the OBSC platform and experience of our team to broaden the utility of the OBSC platform and ultimately improve the care for patients suffering from brain disorders. Our multi-institutional team will bring together and share new disease models, curated panels of therapeutic agents, unique molecular tool kits, and clinical patient tissue. Within the areas of neurodegenerative disease, brain cancers and ischemic disease, we will add disease-relevant capabilities to the platform, screen therapeutic agents, and enable new immune-based approaches, the fastest-growing area of clinical research, with a particular focus on the brain microenvironment. Approaches to accomplish our aims are: (i) We will use OBSC models of neurodegenerative disease to develop methods for tracking of cell signaling using real-time optical imaging, define molecular pathways mediating inflammatory drivers of disease, and identify effective new therapeutic agents. (ii) We will use fresh patient biopsy samples and OBSC models of aggressive brain cancer to characterize he cellular and genomic heterogeneity of brain tumors, the efficacy of anti-cancer immune therapies, and perform drug screens to identify new therapeutic agents. (iii) Lastly, we will utilize OBSC models of ischemic disease to develop methods for pooled molecular screening, investigate the impact of microglia on stroke progression, and identify new compounds that reduce infarct size. Together, our approaches will create an expandable infrastructure built around OBSC technology, accelerate the discovery of new and effective therapeutic strategies, and initiate translation towards ultimate human patient trials to treat multiple disorders of the brain.

项目摘要/摘要脑部疾病仍然是一个巨大的医学挑战。支持功能测试的新平台迫切需要结合患者组织和高通量能力的高保真系统来桥接基于细胞的测试和整体动物测试之间的差距。我们建议通过多机构的努力来识别，利用器官型脑片培养开发和启动神经治疗药物的翻译 (OBSC)平台。我们的OBSC模型利用活脑片中现有的细胞和细胞外环境来允许对脑组织进行快速的功能测试。我们的多学科团队，涵盖三个CTSA项目中心(北卡罗来纳大学、杜克大学和大学(佛罗里达)，已经开发了多种神经障碍模型，并展示了 OBSC平台在发现新的疾病机制和确定新的治疗方法方面的有效性化合物。我们已经为OBSC建模开发了技术创新，包括提高吞吐量脑切片、基于病毒和生物的疾病相关基因、靶向基因的转导技术击倒，使用报告分析进行实时监测，并结合新鲜的患者组织。我们现在寻求利用OBSC平台的力量和我们团队的经验来扩大OBSC的效用平台，最终改善对脑部疾病患者的护理。我们的多机构团队将汇聚并共享新的疾病模型、经过精心策划的治疗剂小组、独特的分子工具试剂盒和临床患者组织。在神经退行性疾病、脑癌和缺血性疾病领域内疾病，我们将在平台上添加与疾病相关的功能，筛选治疗药物，并启用新的以免疫为基础的方法，是临床研究中增长最快的领域，特别关注大脑微环境。实现我们目标的方法是：(I)我们将使用神经退行性变的OBSC模型疾病开发使用实时光学成像跟踪细胞信号的方法，定义分子调节疾病炎症驱动因素的途径，并确定有效的新治疗剂。(Ii)我们会使用新鲜的患者活检样本和侵袭性脑癌的OBSC模型来表征细胞和脑肿瘤的基因组异质性，抗癌免疫治疗的疗效，以及进行药物筛选以确定新的治疗剂。(Iii)最后，我们将利用OBSC缺血性疾病模型来开发联合分子筛查的方法，研究小胶质细胞在卒中进展中的影响，并确定缩小梗塞面积的新化合物。我们的方法将共同创建一个可扩展的基础设施围绕OBSC技术，加速发现新的有效治疗策略，并发起翻译成治疗多种脑部疾病的终极人类患者试验。