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.

总结 与人类相反，一些动物能够在严重受伤后无疤痕地愈合和再生失去的肢体。 再生需要快速和仔细调节细胞增殖，以取代失去的组织， 固有的合成代谢过程。尽管生物合成是再生愈合的一部分， 缺乏对损伤如何与使细胞增殖的代谢变化相结合的机械理解 和增长重新创造能够促进生长的代谢条件对于能够培养 在生物体中的再生成功通常是有限的，比如我们自己。在本提案中，我们 利用两个优点来阐明脊椎动物附肢再生的代谢要求。的 首先是从其他高度增殖的细胞类型中获得的一套机制性见解，这些细胞依赖于有氧糖酵解 将葡萄糖转化为葡萄糖-6-磷酸，这是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，这是一个共同的策略，在附属物再生。第二 是非洲爪蟾蝌蚪附肢再生的独特的环境特异性，这是失去或获得的 营养来源、发育阶段和附肢类型的基础。这种上下文特异性给了我们 有机会直接比较再生结构，以他们的非再生同行和其他非- 再生结构，从而定义代谢景观的具体特征， 再生结果。在这个建议中，我们将测试中心假设，即再生的成功是由 通过组织快速重塑其代谢景观并将营养物质引向生物合成的能力。 我们将通过首先定义在再生条件下占主导地位的代谢范式来测试这一假设： 糖酵解、戊糖磷酸途径或氧化磷酸化。我们会找出共同的背景- 代谢重编程的具体特征，对比再生结构的代谢概况， 非洲爪蟾蝌蚪不同发育阶段的非再生结构。最后，我们得出以下结论： 建立再生中代谢的调控景观，功能测试候选调控 转录因子，并定义代谢基因表达如何在细胞间分配或整合 类型