Why don’t lizards regenerate perfect tails like salamanders?

为什么蜥蜴不能像火蜥蜴那样再生出完美的尾巴？

基本信息

批准号：
10367800
负责人：
Thomas Peter Lozito
金额：
$ 34.65万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10367800
关键词：
Adult Amaze Ambystoma Ambystoma mexicanum Anatomy Animal Model Apoptosis CXCR4 Receptors CXCR4 gene Cartilage Cell Lineage Cell Survival Cells Characteristics Chemotaxis Chondrocytes Complex Development Elements Embryo Environment Epiphysial cartilage Exhibits Funding Generations Goals Homologous Transplantation Human Hypertrophy Immunosuppression Interruption Intervention Knowledge Lead Ligands Lizards Mammals Medicine Meningeal Meninges Molecular Natural regeneration Operative Surgical Procedures Organism Osteoblasts Outcome Pattern Periosteum Phenocopy Physiologic Ossification Population Process Regenerative Medicine Regenerative capacity Research Project Grants Role Salamander Signal Transduction Skeletal Development Skeleton Source Spinal Cord Tail Testing Thyroid Hormones Tissue Engineering Tissues Translating Tube Vertebral column asexual base blastema bone cell cartilage development cartilaginous cellular engineering comparative design healing improved in vivo information model innovation insight knock-down migration notochord novel parathyroid hormone-related protein recruit regenerative skeletal skeletal maturation skeletal regeneration skeletal tissue spatiotemporal tissue regeneration ubiquitin-protein ligase wound environment wound healing

项目摘要

Enhancing regenerative capacities is a fundamental goal in medicine. As yet, the principles of salamander regeneration to augment mammalian healing are not directly applicable. Here we propose using lizards, more closely related to mammals yet exhibiting remarkable regenerative capabilities, as model organisms in a set of studies aimed at manipulating skeletal regeneration capacities. While both salamanders and lizards regenerate their tails, salamanders regenerate near-perfect copies of original tails, while regenerated lizard tails are known as an “imperfect replicates” with several key anatomical differences compared to originals. The most striking of these “imperfections” concerns the lack of dorsoventral patterning and segmentation in regenerated lizard tail skeletons. Progress made under our original proposal identified the signals regulating regenerated skeletal tissue induction and patterning, creating the first dorsoventrally-patterned regenerated lizard tails. This renewal proposal focuses on later stages of skeletal maturation that, given the proper signals, culminate in segmentation. Our recent comparative analyses indicate that regenerated skeleton segmentation is dependent upon three distinct milestones: (1) perichondrium patterning, (2) cartilage hypertrophy, and (3) periosteum formation. Both salamander and lizard regenerated tail skeletons begin as unsegmented cartilage elements. Our preliminary findings suggest a novel role for spinal cord meningeal tissues in regulating skeleton segmentation. Regenerated salamander, but not lizard, meninges contain specialized cell populations capable of recreating embryonic segmentation signals in adjacent perichondrium and initiating a signaling cascade that transforms the entire regenerated skeleton. Some of these signals induce cartilage hypertrophy in salamander cartilage before anti- ossification processes that dominate lizard skeletons have the chance to stagnate cartilage maturation. Other signals missing in lizard tails allow salamander bone cells to survive and promote periosteum development. Based on this comparative analysis, we hypothesize the feasibility of mechanistically based interventions to shift the “imperfectly” regenerating lizard tail to phenocopy the “perfectly” regenerating salamander tail. The Aims are: (1) Introduce patterning to regenerated lizard tail perichondrium by supplementing adult spinal cord meninges with embryonic segmenting cells; (2) Induce regenerated lizard cartilage hypertrophy by interrupting anti- maturation signals that result in dysregulated cartilage development; and (3) Promote periosteum formation within regenerated lizard tails by inducing bone cell survival and recruitment. An integrated approach is proposed, incorporating a unique, asexually reproducing lizard species with in vivo surgical manipulations to deliver cells and bioactive agents toward manipulating skeletal development. We believe that this approach will produce the first regenerated lizard tails with skeletons exhibiting cartilage maturation and segmentation. These studies will contribute towards mechanistic understanding of a vertebrate regenerative process, and may lead to improving skeletal healing in non-regenerative organisms, including humans.

增强再生能力是医学的基本目标。到目前为止，Salamander的原则再生以增强哺乳动物的愈合不适用。在这里，我们建议使用蜥蜴，更多与哺乳动物密切相关，但表现出显着的再生能力，作为一组模型生物旨在操纵骨骼再生能力的研究。而萨拉曼和蜥蜴都再生他们的尾巴，sal酱再生原始尾巴的近乎完美的副本，而再生蜥蜴尾巴是已知的作为“不完美的重复”，与原始作品相比，有几种关键的解剖学差异。最引人注目的这些“瑕疵”涉及再生蜥蜴尾巴缺乏背腹图案和细分骨骼。根据我们的原始提案取得的进展确定了重新生成的骨骼组织的信号诱导和图案，创建了第一个背面的再生蜥蜴尾巴。这个更新提案的重点是骨骼成熟的后期阶段，鉴于适当的信号，该阶段在分割中达到了最终形式。我们最近的比较分析表明，再生骨骼分割取决于三个不同的里程碑：（1）peri骨模式，（2）软骨肥大和（3）骨膜形成。两个都 Salamander和Lizard再生的尾骨骨骼以未分段的软骨元素开始。我们的初步发现表明，脊髓脑膜组织在调节骨骼分割中的新作用。再生 Salamander，但不是蜥蜴，脑膜包含能够重新创建胚胎的专门细胞种群相邻perichondrium中的分割信号，并启动一个信号级联，以改变整个再生骨骼。这些信号中的某些信号在抗sal骨软骨中诱导软骨肥大主导蜥蜴骨骼的骨化过程有机会停滞软骨成熟。其他蜥蜴尾部缺少的信号使Salamander骨细胞能够生存并促进骨膜发育。基于这种比较分析，我们假设基于机械的干预措施的可行性 “不完美的”再生蜥蜴尾巴，以表观“完美”再生Salamander尾巴。目的是：（1）通过补充成人脊髓销售物来将图案介绍给再生蜥蜴尾巴的尾巴与胚胎分割细胞；（2）通过中断抗 - 成熟信号导致软骨发育失调；（3）促进骨膜形成通过诱导的骨细胞存活和募集在重生的蜥蜴尾巴中。综合方法是提出的，纳入了一种独特的，无性繁殖的蜥蜴物种，并带有体内手术操纵传递细胞和生物活性剂来操纵骨骼发育。我们相信这种方法将产生第一个带有软骨成熟和分割的骨骼的再生蜥蜴尾巴。这些研究将有助于对脊椎动物再生过程的机械理解，并可能导致改善包括人类在内的非再生生物的骨骼愈合。