Translational platform for epilepsy therapy and biomarker discovery

癫痫治疗和生物标志物发现的转化平台

基本信息

批准号：
10467726
负责人：
Denes V. Agoston
金额：
$ 222.91万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467726
关键词：
Acute Address Advisory Committees Advocate Anatomy Animal Model Animals Antiepileptogenic Autophagocytosis Axon Bioinformatics Biological Markers Blood Blood Vessels Brain Brain Pathology Calcium-Binding Proteins California Caring Cell Death Cessation of life Clinical Collaborations Corpus Callosum Data Deposition Development Discriminant Analysis Disease Double-Blind Method Early Post-Traumatic Seizures Early treatment Electroencephalography Epilepsy Epileptogenesis External Capsule Free Radicals Funding Future Glial Fibrillary Acidic Protein Guidelines HMGB1 Protein Hemorrhage High Frequency Oscillation Image Inflammatory Injury Interferon Type II Interferons Interleukin-1 International Intervention Investigation Iron Iron Chelating Agents Isoenzymes Laboratories Lateral Learning Levetiracetam Link Machine Learning Magnetic Resonance Imaging Medicine Memory Metabolic Minnesota Modeling Modification Molecular Monitor Motor National Institute of Neurological Disorders and Stroke Neuroglia Neurons Oxidative Stress Pathologic Pathology Patients Peripheral Persons Pharmaceutical Preparations Physiological Plasma Post-Traumatic Epilepsy Pre-Clinical Model Preclinical Testing Predictive Value Process Randomized Rattus Recovery of Function Research Risk Risk Factors Seizures Site Testing Therapeutic Time Tissues Translational Research Traumatic Brain Injury Universities University Health Services Visuospatial acquired epilepsy base biomarker discovery biomarker panel brain magnetic resonance imaging candidate marker clinical practice college design early detection biomarkers efficacy testing experience fluid percussion injury functional outcomes high standard histological stains in vivo multimodality neuroimaging novel novel marker pharmacokinetic model pre-clinical predictive marker prevent primary endpoint prophylactic protein biomarkers standard of care synergism tau Proteins tau-1 treatment response ubiquitin C-terminal hydrolase

项目摘要

PROJECT SUMMARY There is currently no validated treatment to prevent the development of acquired epilepsies, such as post- traumatic epilepsy. The availability of biomarker that predicts, at an early stage, people at risk to develop epilepsy and benefit from treatment interventions would significantly accelerate and de-risk the process of identifying an antiepileptogenic therapy. In this study, that is based on collaborations and preliminary data derived from EpiBioS4Rx, an NINDS funded Center without Walls, we aim to create a rigorous and effective preclinical model to screen a new candidate treatment to prevent posttraumatic epilepsy in the lateral fluid percussion injury model as well as identify biomarkers to guide treatment implementation. We will follow a multicenter, double-blinded, vehicle-controlled, randomized preclinical antiepileptogenesis study following the high standards of rigor advocated by NINDS, the AES/ILAE Translational Research Task Force and the ARRIVE guidelines. We have formed a collaborative group of four international preclinical testing centers (Albert Einstein College of Medicine, University of Melbourne, two UCLA sites), supported by experts in pharmacokinetic modeling (University of Minnesota), protein biomarker research (Uniformed Services University of the Health Services) and bioinformatics (University of Southern California). We plan to test a compound that removes pathological iron stores from the brain and test whether it can modify early biomarkers of epileptogenesis and injury. We aim to identify (a) at least one panel of multimodal biomarkers that can predict early on treatment response to the iron chelator, including the development of post-traumatic epileptogenesis, (b) at least one biomarker of epileptogenesis, (c) and determine whether iron chelator treatment can prevent post-traumatic epilepsy development.

项目概要目前尚无有效的治疗方法可以预防获得性癫痫的发展，例如癫痫后遗症。外伤性癫痫。可在早期阶段预测有癫痫风险的人的生物标志物的可用性治疗干预措施的好处将显着加速并降低识别风险的过程抗癫痫治疗。在这项研究中，这是基于合作和来自以下来源的初步数据： EpiBioS4Rx是NINDS资助的无墙中心，我们的目标是创建严格有效的临床前模型在侧方液体冲击损伤模型中筛选一种新的候选治疗方法以预防创伤后癫痫以及确定生物标志物来指导治疗的实施。我们将遵循多中心、双盲、遵循高严格标准的车辆对照、随机临床前抗癫痫发生研究由 NINDS、AES/ILAE 转化研究工作组和 ARRIVE 指南倡导。我们有成立了一个由四个国际临床前测试中心（阿尔伯特·爱因斯坦医学院、墨尔本大学、加州大学洛杉矶分校的两个分校），得到药代动力学建模专家的支持（墨尔本大学明尼苏达州），蛋白质生物标志物研究（卫生服务制服服务大学）和生物信息学（南加州大学）。我们计划测试一种去除病理性铁的化合物从大脑中储存并测试它是否可以修改癫痫发生和损伤的早期生物标志物。我们的目标是确定 (a) 至少一组多模式生物标志物，可以早期预测对铁剂的治疗反应螯合剂，包括创伤后癫痫发生的发展，(b) 至少一种生物标志物癫痫发生，(c) 并确定铁螯合剂治疗是否可以预防创伤后癫痫发展。