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Combinatorial Manipulation of Transcription Factors to Promote CNS Regeneration

转录因子的组合操作促进中枢神经系统再生

基本信息

批准号：
9890010
负责人：
Murray G Blackmore
金额：
$ 37.96万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890010
关键词：
3-Dimensional Adult Age Anatomy Animal Model Animals Axon Behavior assessment Behavioral Brain Brain Stem Brain region Cell Culture Techniques Cell Transplantation Cell physiology Cervical Corticospinal Tracts Cre driver DNA Data Data Collection Development Disease Electrophysiology (science)Embryo Environment Failure Family Family member Gene Delivery Gene Expression Gene Transduction Agent Genes Growth Individual Injections Injury Intervention Lead Methods Microscopy Midbrain structure Modeling Motor Cortex Mus NR5A2 gene Natural regeneration Nerve Regeneration Nervous system structure Neuraxis Neuronal Injury Neurons Population Population Heterogeneity Production Property RARB gene Recovery Recovery of Function Research Residual state Rodent Model Site Speed Spinal Cord Spinal Injuries Spinal cord injury Stem cell transplant Surveys Synapses System Testing Therapeutic Three-Dimensional Imaging Tissues Transplantation Trauma Treatment Factor Viral axon growth axon injury axon regeneration base bioinformatics pipeline cell type central nervous system injury clinical translation combinatorial disability effective therapy experimental study falls functional gain functional restoration gene therapy improved in vivo evaluation injured nerve injury novel optogenetics prevent programs regenerative screening stem cells success synaptogenesis synergism therapeutic target tool transcription factor vector

项目摘要

PROJECT SUMMARY In adults, axons in the central nervous system (CNS) generally fail to regenerate after they are lost to injury or disease, leading to permanent and incurable disability. Axon growth is prevented by a hostile growth environment, as well as a developmental loss in the intrinsic capacity for axon growth as CNS neurons age. Transcription factors (TFs) interact with DNA and coordinate the production of broad sets of cellular materials, and have emerged as important therapeutic targets to boost regenerative ability within injured neurons. For example, forced re-expression of a pro-regenerative TF called KLF6 in adult neurons can improve their capacity for axon growth after spinal injury. We will now test three complementary and mutually supportive strategies to enhance the promising pro-regenerative properties of KLF6. First, using a novel bioinformatics pipeline, we have predicted additional TFs that functionally interact with KLF6 and verified their ability to synergistically enhance axon growth when combined with KLF6 in cell culture models of axon growth. We will therefore perform in vivo tests of three selected factors, EOMES, NR5A2, and RARB, for the ability to enhance KLF6’s pro-regenerative properties in animal models of spinal cord injury. Second, we will supplement these TF interventions with transplants of growth- permissive stem cells into sites of spinal injury. These grafts will alleviate persistent growth inhibition in the spinal cord environment, and thus unmask the pro-regenerative effects of TF treatments. Finally, we will harness a newly developed gene therapy vector that enables retrograde delivery of genes with unprecedented efficiency. Injection of this vector to the spinal cord results in widespread gene expression in injured neurons throughout the brainstem, midbrain, and motor cortex. This delivery system engages a larger number and a wider diversity of cell types than the current practice of direct brain injection, thus maximizing the chance of achieving functional gains after spinal injury. Throughout these aims, tissue clearing and 3D microscopy will reveal new anatomical details of the evoked regeneration. Bringing together these cutting-edge improvements to a TF-centered strategy will move the field toward novel and effective treatments for individuals suffering from the debilitating consequences of CNS injury.

项目总结