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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.

项目总结/文摘