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The transcription factor HHEX as a novel regulator of CNS axon regeneration

转录因子 HHEX 作为中枢神经系统轴突再生的新型调节因子

基本信息

批准号：
9018774
负责人：
Murray G Blackmore
金额：
$ 23.38万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9018774
关键词：
Address Adult Animal Model Axon Behavioral Brain Cells Cervical ChIP-seq Data Data Set Disease Excision Failure Foundations Gene Expression Gene Targeting Genes Genetic Transcription Goals Grant Growth Injection of therapeutic agent Injury Intervention Knock-out Knowledge Lead Link Mammals Mechanics Modeling Molecular Morphology Mus Mutation Natural regeneration Nerve Regeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Patients Peripheral Peripheral Nervous System Phenotype Process Recovery Regenerative response Regulation Repression Rodent Model Role Spinal Cord Spinal cord injury Stroke Structure Synthetic Genes System Testing Therapeutic Therapeutic Intervention Transgenic Mice Trauma Traumatic Brain Injury Tumor Suppression United States VP 16 Vertebrates Viral Work axon growth axon injury axon regeneration axonal sprouting base cell growth central nervous system injury gene repression improved in vivo inhibitor/antagonist injured insight mutant neural circuit novel novel strategies overexpression prevent programs public health relevance regenerative relating to nervous system repaired research study response screening stroke recovery success transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Here we seek to clarify the molecular mechanisms by which a transcription factor called HHEX restricts the ability of neurons to extend axons, and explore the potential of interfering with HHEX function to promote axon growth in the central nervous system. This work is significant because the low regenerative ability of neurons in the central nervous system prevents full recovery from stroke, neurodegenerative disease, or injury to the brain or spinal cord. A major therapeutic goal is to enhance regenerative ability in CNS neurons, but the molecular mechanisms that restrict growth remain incompletely understood. HHEX, which has been linked to cellular growth in cells outside the nervous system but is largely unstudied in the brain, emerged unexpectedly from a large-scale screening experiment that examined the effect of various transcription factors on the morphology of cortical neurons. Expression of HHEX strongly decreases axon growth. Furthermore, HHEX is expressed in adult CNS neurons that regenerate poorly, but not in regeneration-competent neurons in the peripheral nervous system. Finally, a structure-function analysis revealed that HHEX blocks axon growth by suppressing target genes, and that an artificial construct that activates HHEX target genes reverses the normal activity, that is, enhances axon growth. Combined, these data suggest that HHEX acts as a novel factor that suppresses axon growth ability in CNS neurons, and that manipulating HHEX function can promote axon growth. In this grant we will 1) clarify the set of genes that are regulated by HHEX in order to clarify the mechanism of growth suppression and 2) test the ability of HHEX-based manipulations to promote axonal sprouting and regeneration in an animal model of spinal cord injury. Ultimately, these studies will fill a critical gap in knowledge in the field through the identification of novel transcriptional components that regulate CNS regeneration, and explore the potential of this new target to improve regenerative capacity.