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

• 批准号: 9132364
• 负责人: Murray G Blackmore
• 金额: $ 19.48万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132364
• 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; Health; 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; regenerative; relating to nervous system; repaired; research study; response; screening; stroke recovery; success; transcription factor; transcriptome sequencing

 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.

 描述（由申请人提供）：在这里，我们试图阐明一种名为 HHEX 的转录因子限制神经元延伸轴突的能力的分子机制，并探索干扰 HHEX 功能促进中枢神经系统轴突生长的潜力。这项工作意义重大，因为中枢神经系统中神经元的低再生能力阻碍了中风、神经退行性疾病或大脑或脊髓损伤的完全恢复。主要的治疗目标是增强中枢神经系统神经元的再生能力，但限制生长的分子机制仍不完全清楚。 HHEX 与神经系统外细胞的生长有关，但在大脑中基本上没有被研究过，它在一项大规模筛选实验中意外出现，该实验检查了各种转录因子对皮质神经元形态的影响。 HHEX 的表达强烈降低轴突生长。此外，HHEX 在再生能力较差的成年 CNS 神经元中表达，但在周围神经系统中具有再生能力的神经元中不表达。最后，结构功能分析表明，HHEX 通过抑制靶基因来阻止轴突生长，而激活 HHEX 靶基因的人工构建体会逆转正常活性，即增强轴突生长。综合起来，这些数据表明 HHEX 作为一种抑制 CNS 神经元轴突生长能力的新因子，并且操纵 HHEX 功能可以促进轴突生长。在这笔资助中，我们将 1) 阐明 HHEX 调控的一组基因，以阐明生长抑制机制；2) 测试基于 HHEX 的操作在脊髓损伤动物模型中促进轴突萌芽和再生的能力。最终，这些研究将通过鉴定调节中枢神经系统再生的新型转录成分，填补该领域知识的关键空白，并探索这一新靶点提高再生能力的潜力。

项目成果

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo.

• DOI: 10.1016/j.nepig.2016.10.002
• 发表时间: 2016-12
• 期刊: Neuroepigenetics

Developmental Chromatin Restriction of Pro-Growth Gene Networks Acts as an Epigenetic Barrier to Axon Regeneration in Cortical Neurons.

• DOI: 10.1002/dneu.22605
• 发表时间: 2018-10
• 期刊: Developmental neurobiology
• 影响因子: 3
• 作者: Venkatesh I;Mehra V;Wang Z;Califf B;Blackmore MG
• 通讯作者: Blackmore MG

The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons.

• DOI: 10.1016/j.mcn.2015.08.008
• 发表时间: 2015-09
• 期刊: Molecular and cellular neurosciences
• 作者: Simpson MT;Venkatesh I;Callif BL;Thiel LK;Coley DM;Winsor KN;Wang Z;Kramer AA;Lerch JK;Blackmore MG
• 通讯作者: Blackmore MG