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Translational medicine and mechanistic studies of brain neurophysiology in Fragile X Syndrome

脆性 X 综合征脑神经生理学的转化医学和机制研究

基本信息

批准号：
10453460
负责人：
Craig Erickson
金额：
$ 160万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453460
关键词：
Address Animal Experiments Animal Model Back Behavior Behavioral Biological Markers Biology Brain Cholecystokinin Clinical Clinical Research Clinical Sciences Clinical Trials Cognition Collaborations Data Development Disease Drug Monitoring Electroencephalography Electrophysiology (science)Endocannabinoids Ensure Environment Eye FMR1 FMRP Failure Fostering Foundations Fragile X Syndrome Future Gene Proteins Glutamates Goals Heterogeneity Human Interneurons Investigation Knockout Mice Knowledge Link Measures Methodology Mission Modeling Molecular Molecular Analysis Mus Neocortex Neurobiology Neurons Neurosciences Research Patient Monitoring Patients Persons Pharmaceutical Preparations Pharmacology Phenotype Physiology Preparation Principal Investigator Research Risk Role Slice Speed Stimulus Surface Technology Testing Therapeutic Effect Time Translations Work base bench to bedside biomarker development brain dysfunction clinically relevant design drug development effective therapy endocannabinoid signaling endogenous cannabinoid system experience gene therapy human study improved in vivo individualized medicine insight interest molecular modeling multi-electrode arrays multidisciplinary network models neural circuit neurobehavioral neurophysiology neurotransmission novel novel therapeutics patient oriented patient stratification personalized medicine pre-clinical pre-clinical research preclinical study predictive marker programs protein expression receptor response small molecule success therapy development translational medicine

项目摘要

Over the last six years our project teams have demonstrated that neurophysiology abnormalities are conserved across mice and humans in fragile X syndrome (FXS). These findings across species provide a great opportunity to advance mechanistic understanding of clinically relevant illness features and develop translational biomarkers and aid treatment discovery. These advances can bridge the significant chasm between preclinical and clinical success in new treatment development. We take mechanistic approaches to determining the drivers of neurophysiology dysregulation across three integrated projects spanning human, in vivo, and ex vivo mouse study. This allows for levels of analysis from whole brain network modeling to microcircuit and molecular analysis to aid target discovery while improving translational medicine efforts in FXS. In doing this we place emphasis on recognizing heterogeneity within FXS and using this understanding to model how to best interpret and link preclinical and clinical study. Out of this appreciation of the challenges to translational efforts in our field, we have developed a synchronized approach to the analysis and interpretation of neurophysiology data ensuring comparable results across research platforms. The striking consistency of findings across levels of investigation and species offers an unprecedented opportunity to investigate mechanisms of brain dysfunction across mouse and human study thus significantly improving opportunities for translational medicine development in FXS- a multidisciplinary mission that is ideal for a Center environment. Project 1 (Erickson/Sweeney; Cincinnati) will conduct human FXS neurophysiology, behavior, and pharmacological probe studies to pursue advanced neurophysiology modeling of cortical hyperexcitability and abnormal response to stimuli while also seeking to resolve heterogeneity across FXS in humans. Project 2 (Binder/Razak; Riverside) will develop translational neurophysiological biomarkers for FXS in the Fmr1 KO mouse using both surface and depth multi-electrode array technology. Project 3 (Huber/Gibson, UTSW) will investigate the microcircuit and molecular mechanisms of neurophysiologic dysregulation in the Fmr1 KO mouse. All Projects will examine candidate mechanisms of neurophysiologic dysregulation with a pharmacological probe strategy to test mechanisms of interest in parallel studies of mice and patients.

在过去的六年里，我们的项目组已经证明了神经生理异常