Transcriptional regulatory mechanisms of vertebrate regeneration

脊椎动物再生的转录调控机制

• 批准号: 10594191
• 负责人: Andrea Elizabeth Wills
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594191
• 关键词: ATAC-seq; Adult; Articulation; Atlases; Biological Metamorphosis; Biological Models; Cell Cycle; Cells; Competence; Complex; Cues; DNA; Data; Dorsal; Embryo; Embryonic Development; Engraftment; Epigenetic Process; Failure; Functional Regeneration; Gene Targeting; Genetic Transcription; Goals; Human; Injury; Modeling; Molecular; Motor Neurons; Natural regeneration; Nerve Regeneration; Neural tube; Neurons; Outcome; PBX3 gene; Patients; Pattern; Population; Positioning Attribute; Proliferating; Property; Proteins; Rana; Regenerative Medicine; Regulation; Resolution; Signal Transduction; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Structure; System; Systems Analysis; Tadpoles; Testing; Therapeutic; Work; Xenopus; cell type; functional restoration; healing; improved; loss of function; nerve stem cell; neural; novel; novel therapeutic intervention; programs; regeneration model; regenerative; regenerative biology; response to injury; single-cell RNA sequencing; spatiotemporal; spinal cord regeneration; stem cells; success; targeted imaging; targeted treatment; transcription factor; transcription regulatory network

SUMMARY In many species, spinal cord regeneration is driven by the proliferation and differentiation of neural progenitor cells (NPCs), but therapeutic efforts to promote regeneration in human patients through engraftment of neural stem cells or progenitor cells have had limited success. These limitations arise in part because the cell-intrinsic properties of NPCs and neurons that enable natural regeneration are still largely undefined, as are the spatial cues that confer positional identity on these cells in a regenerative context. Tadpoles of the frog Xenopus tropicalis can respond to major spinal cord injury with scarless healing and regeneration, a capability that is lost as the tadpole completes metamorphosis. This stage-specific regenerative competence represents a uniquely sensitive system in which to define the transcriptional regulatory profile of NPCs and neurons that support regeneration, and the incremental changes in all spinal cord cells that contribute to regenerative loss. In this project, we will test the central hypothesis that regenerative competence is dictated by the ability of NPCs to respond to injury by transcriptionally activating spatiotemporally distinct programs of proliferation or neuronal subtype differentiation. Our project examines this hypothesis from three standpoints. First, we will ask how the spatial organization of the spinal cord, and specifically NPC domains, is re-established after injury, explicitly asking whether embryonic patterning cues along the dorsal-ventral axis are recapitulated. Second, we will define the functions of two new transcriptional regulators of spinal cord regeneration that we have identified, Pbx3 and Meis1, identifying the gene targets, sensitive cell types, and protein interactions of these two TALE box transcription factors contrast between embryonic development and regeneration. Finally, we will test specific hypotheses for how regeneration fails by contrasting the cell intrinsic changes in NPCs and neurons that occur in response to injury in regenerative versus non-regenerative stages. By completing this project we will fundamentally advance our understanding of how regeneration is achieved and how it is lost in this closely- related vertebrate, opening the door for new therapeutic strategies informed by this naturally occurring model of regeneration.

总结 在许多物种中，脊髓再生是由神经祖细胞的增殖和分化驱动的 细胞（NPC），但治疗努力，以促进再生的人类患者通过移植的神经 干细胞或祖细胞的成功有限。这些限制的出现部分是因为细胞内在的 能够自然再生的NPC和神经元的特性在很大程度上仍然不确定，空间也是如此。 在再生环境中赋予这些细胞位置同一性的线索。非洲爪蟾的蝌蚪 Tropicalis可以对严重的脊髓损伤做出无瘢痕愈合和再生的反应， 当蝌蚪完成蜕变时。这种特定阶段的再生能力代表了一种独特的 敏感的系统，在其中定义的NPC和神经元，支持转录调控模式 再生，以及所有脊髓细胞中导致再生损失的增量变化。在这 项目，我们将测试中心假设，即再生能力是由NPC的能力， 通过转录激活时空上不同的增殖程序或神经元细胞增殖程序来响应损伤。 亚型分化我们的项目从三个角度来检验这个假设。首先，我们会问， 脊髓的空间组织，特别是NPC区域，在损伤后重建， 询问胚胎图案线索是否沿背腹轴沿着重演。二是 定义我们已经鉴定的两种新的脊髓再生转录调节因子的功能， Pbx 3和Meis 1，鉴定这两种TALE的基因靶标、敏感细胞类型和蛋白质相互作用 box转录因子在胚胎发育和再生之间的差异。最后，我们将测试 通过对比NPC和神经元的细胞内在变化， 在再生和非再生阶段对损伤的反应。通过完成这个项目，我们 将从根本上推进我们对再生如何实现以及如何在这一紧密联系中失去的理解- 相关的脊椎动物，打开大门，新的治疗策略，告知这种自然发生的模型 重生的机会