Decoding the metabolic requirements for vertebrate appendage regeneration

解码脊椎动物附肢再生的代谢需求

• 批准号: 10564466
• 负责人: Andrea Elizabeth Wills
• 金额: $ 41.93万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564466
• 关键词: Anabolism; Animal Model; Animals; Articulation; Biological Metamorphosis; Carbon; Cell Proliferation; Cells; Cellular Structures; Complex; Consumption; Coupled; Data; Data Set; Development; Enzymes; Fostering; Future; Gene Expression; Genetic Transcription; Glucose; Glucose-6-Phosphate; Glycolysis; Goals; Growth; Human; Injury; Knowledge; Limb structure; Link; Metabolic; Metabolism; Modeling; Natural regeneration; Nucleotides; Nutrient; Organism; Outcome; Oxidative Phosphorylation; Pathway interactions; Pattern; Pentosephosphate Pathway; Phospholipids; Population; Process; Production; Proliferating; Rana; Regenerative Medicine; Solid Neoplasm; Source; Specificity; Structure; Tadpoles; Tail; Testing; Time; Tissues; Tumor Stem Cells; Warburg Effect; Work; Xenopus; aerobic glycolysis; appendage; cell growth; cell type; embryonic stem cell; experimental study; feeding; glucose uptake; healing; human tissue; insight; limb regeneration; metabolic profile; programs; regeneration model; regenerative; single cell analysis; stem cells; success; tissue regeneration; transcription factor

SUMMARY In contrast to humans, some animals are able to scarlessly heal and regrow lost appendages after major injury. Appendage regeneration requires rapid and carefully regulated cell proliferation to replace lost tissue, an inherently anabolic process. Despite the fundamental need for biosynthesis as part of regenerative healing, we lack a mechanistic understanding of how injury is coupled to metabolic changes that enable cell proliferation and growth. Re-creating the metabolic conditions that enable growth is critical to being able to foster regenerative success in organisms where it is normally limited, such as ourselves. In this proposal, we leverage two advantages to articulate the metabolic requirements for vertebrate appendage regeneration. The first is a suite of mechanistic insights from other highly proliferative cell types, which rely on aerobic glycolysis to convert glucose to glucose-6-phosphate, a versatile biosynthetic precursor for nucleotide and phospholipid production. Our preliminary data suggest that this is a shared strategy in appendage regeneration. The second is the unique context-specificity of appendage regeneration in Xenopus tadpoles, which is lost or gained on the basis of nutrient source, developmental stage, and appendage type. This context specificity gives us the opportunity to directly compare regenerative structures to their non-regenerative counterparts and to other non- regenerative structures, thereby defining the specific features of the metabolic landscape that enhance or limit regenerative outcome. In this proposal we will test the central hypothesis that regenerative success is dictated by the ability of tissues to rapidly remodel their metabolic landscape and funnel nutrients toward biosynthesis. We will test this hypothesis by first defining the metabolic paradigm that dominates in regenerative conditions: glycolysis, pentose phosphate pathway, or oxidative phosphorylation. We will then identify shared and context- specific features of metabolic reprogramming, contrasting the metabolic profile of regenerative structures and non-regenerative structures at different developmental stages of the Xenopus tadpole. We conclude by building a regulatory landscape of metabolism in regeneration, functionally testing candidate regulatory transcription factors, and defining how metabolic gene expression is partitioned or integrated between cell types.

概括 与人类相反，一些动物能够无稀有的愈合，并在重大受伤后失去附属物。 附录再生需要快速，仔细调节的细胞增殖才能替代失去的组织 天生的合成代谢过程。尽管作为再生愈合的一部分，对生物合成的基本需求，我们 缺乏对损伤如何与代谢变化耦合的机械理解，从而使细胞增殖能够 和增长。重新创造能够增长的代谢条件对于能够培养至关重要 在通常受到限制的生物体中的再生成功，例如我们自己。在这个建议中，我们 利用两个优势来阐明脊椎动物附属再生的代谢要求。这 首先是来自其他高度增殖细胞类型的一系列机械见解，这些见解依赖有氧糖酵解 将葡萄糖转化为葡萄糖-6-磷酸盐，核苷酸和磷脂的多功能生物合成前体 生产。我们的初步数据表明，这是附属物再生中的共同策略。第二个 是Xenopus t的附属物再生的独特上下文特异性，它在 营养来源，发育阶段和附属类型的基础。这种上下文特异性使我们 将再生结构与其非再生对应物以及其他非 - 再生结构，从而定义了增强或限制的代谢景观的特定特征 再生结果。在该提案中，我们将检验重新生产成功的中心假设 通过组织快速重塑其代谢景观并将营养成生物合成的能力。 我们将通过首先定义在再生条件下主导的代谢范式来检验这一假设： 糖酵解，磷酸五磷酸途径或氧化磷酸化。然后，我们将确定共享和上下文 - 代谢重编程的特定特征，与再生结构的代谢谱和 在爪蟾t的不同发育阶段的非再生结构。我们结束了 在再生中建立新陈代谢的调节景观，在功能上测试候选监管 转录因子，并定义代谢基因表达如何分配或整合细胞之间 类型。