The role of core circadian regulator Bmal1 in axonal regeneration and nerve repair

核心昼夜节律调节因子 Bmal1 在轴突再生和神经修复中的作用

• 批准号: 10677932
• 负责人: Hongyan Zou
• 金额: $ 57.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677932
• 关键词: ARNTL gene; Acceleration; Address; Affect; Afferent Neurons; Agonist; Axon; Axotomy; Basic Science; Binding; Bioinformatics; Biological Assay; Brain-Derived Neurotrophic Factor; Chromatin; Clinical; Cohort Studies; Collaborations; DNA mapping; Data; Enzymes; Epigenetic Process; Exhibits; Gatekeeping; Genes; Genetic; Genetic Transcription; Hour; Immune; Immune response; Immunologics; In Vitro; Injury; Investigation; Knockout Mice; Laboratories; Link; Maps; Mediating; Metabolism; Modeling; Molecular; Mus; Natural regeneration; Nerve Regeneration; Neurites; Neuroimmune; Neurons; Output; Pathway interactions; Penetration; Periodicity; Peripheral; Peripheral nerve injury; Phase; Phenotype; Pilot Projects; Process; Reconstructive Surgical Procedures; Regenerative response; Regulation; Reporting; Rest; Role; Series; Sex Differences; Shapes; Signal Transduction; Spinal Ganglia; Testing; Time; Work; axon growth; axon injury; axon regeneration; beta catenin; cell type; circadian; circadian biology; circadian pacemaker; comparative efficacy; conditional knockout; design; effective therapy; efficacy evaluation; gene induction; genome-wide; genomic locus; immune activation; in vivo; inhibitor; insight; nerve injury; nerve repair; neural; novel; pharmacologic; programs; recruit; regenerative; repaired; response; sciatic nerve injury; sex; transcription factor; transcriptomics

Project Summary Axon regeneration after peripheral nerve (PN) injury is often incomplete. There is currently no effective treatment beyond surgical reconstruction, which is only beneficial for a small percentage of cases. Understanding the repair mechanisms is thus crucial. Here, we investigate a previously unknown function of the core circadian regulator Bmal1 in gating neuroregenerative responses after PN injury. The study is based on our new data that neuron-specific deletion of Bmal1 accelerates axon regeneration after PN injury. This exciting finding was made in the context of a series of advances from our laboratory in deciphering transcriptional networks that control neuronal intrinsic axon growth potential, i.e., how transcription factors (TFs) cooperate with epigenetic factors to reshape the chromatin landscape for induction of regeneration- associated genes (RAGs). Our most recent work has leveraged our genome-wide mapping of DNA hydroxymethylation (5hmC) dynamics in regenerating dorsal root ganglia (DRG) neurons. Intriguingly, we discovered enrichment of the Bmal1 binding motifs in genomic loci displaying 5hmC changes after PN injury, suggesting an interaction of Bmal1 with the 5mC/5hmC converting enzyme Tet3. Indeed, Bmal1 cKO in mice showed that the Bmal1-Tet3-5hmC axis regulates genes linked to axon growth, metabolism, and immune interactions. Moreover, pilot data show for the first-time a diurnal epigenetic rhythm of Tet3 and 5hmC in DRG neurons that is anti-phasic to Bmal1 transcriptional oscillation and corresponds to time-of-day differences in regenerative responses. Here, we will test the central hypothesis that Bmal1 functions as an inhibitor of axon regeneration and a gatekeeper of injury-trigged immune activation via regulation of 5hmC reprogramming. In Aim 1, we will characterize Bmal1-gated regenerative gene programs and examine the effect of pharmacological inhibition of Bmal1 transcription by SR9009, a potent Rev-Erb agonist with CNS penetration capability. Mechanistically, we will test a “two-hit model” wherein Bmal1 deletion primes DRG neurons, but an injury signal is required for RAGs induction. In Aim 2, we will characterize Tet3/5hmC epigenetic rhythmicity, correlation with “neurite outgrowth clock”, and the underlying mechanisms by testing the working model that Bmal1 controls Tet3 expression as well as Tet3 recruitment to target loci for 5hmC reprogramming. We will then map short- and long-term impact of PN injury on Bmal1-Tet3-5hmC rhythmicity and whether these rhythms return to normal upon axonal reconnection. In Aim 3, we pivot to in vivo study of the promoting effect of Bmal1 inhibition on nerve repair, including motosensory functions. We will also address sustainability of the effect, sex differences, and timed Bmal1 inhibition shortly after PN injury. In sum, our proposal has the potential of connecting Bmal1 circadian pathway, Tet3/5hmC epigenetic reprogramming, injury-triggered immune responses, and axon regeneration, thus advancing basic science of nerve regeneration and opening translational paths.

项目总结