Identifying the genetic changes which induce tissue and organ regeneration in a novel mammalian model system.

识别在新型哺乳动物模型系统中诱导组织和器官再生的遗传变化。

• 批准号: 9226315
• 负责人: Malcolm Maden
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226315
• 关键词: Acomys; Adult; Adverse effects; Biological Models; Blood Cells; Cartilage; Cells; Cicatrix; Code; Collagen; Community Medicine; Comparative Genomic Analysis; Complex; Data; Defect; Deposition; Dermis; Development; Distant; Ear; Elements; Epigenetic Process; Epithelium; European; Excision; Fibrosis; Gene Family; Genes; Genetic; Genome; Genomic approach; Genomics; Gland; Goals; Hair; Hair follicle structure; Heart; Human; Knowledge; Lead; Life; Maintenance; Mammals; Medicine; MicroRNAs; Modeling; Molecular; Mus; Mutation; Natural regeneration; Organ; Organism; Outcome; Phenotype; Physiological; Play; Predatory Behavior; Process; Property; Public Domains; Publishing; Rattus; Reaction; Regenerative Medicine; Regulator Genes; Research; Research Infrastructure; Resources; Rodent; Sebaceous Glands; Skeletal Muscle; Skin; Skin Tissue; Skin wound; Smooth Muscle; Spinal Cord; Spinal cord damage; Structure; Synteny; Therapeutic; Thick; Tissue Microarray; Tissues; Translating; Work; Wound Healing; base; comparative genomics; effective therapy; in vivo; muscle regeneration; new therapeutic target; novel; organ regeneration; prevent; programs; regenerative; repaired; response; response to injury; therapeutic development; tissue regeneration; tissue repair; whole genome

PROJECT SUMMARY The long-term goal of this project is to explore and validate the spiny mouse, Acomys, as a new and unique model system for understanding the molecular, cellular and tissue level mechanisms of reparative regeneration in mammals and to translate this knowledge to the development of novel concepts for therapeutic regeneration. Acomys can regenerate a staggering range of tissues in a scar-free manner after full thickness skin wounding: smooth muscle, skeletal muscle, dermis, hair, glands; additionally it can regenerate cartilage after ear punches; and uniformly displays little or no fibrosis during skeletal muscle regeneration, heart damage or spinal cord damage. We hypothesize that this lack of fibrotic reaction is a fundamental property of the cells of this organism because the genetic controls of collagen deposition and other matrix molecules have evolved differently to generate a weak-skinned phenotype which has major advantages to the survival of this species following prey attack. As a consequence, in response to damage the altered collagen fibrotic response permits endogenous regenerative mechanisms to come into play. The aims of this application are to generate a de novo whole genome sequence of Acomys so that we can perform comparative genomics to reveal the controls of collagen and matrix deposition either in coding or regulatory sequences following tissue damage. This work will enable the field to investigate the relation between fibrosis and regeneration and to generate an infrastructure from which to adapt and develop translational ideas for therapeutic regeneration in humans. RELEVANCE The ability to regenerate complex tissues and organs in a scar-free manner is the holy grail of regenerative medicine, but we currently have no mammalian model with which to investigate the cellular and molecular processes involved. We have discovered a new mammal, the spiny mouse, which can regenerate many tissues without inducing fibrosis and in this proposal we intend to uncover the genetic controls on regenerative mechanisms used by this organism for reparative regeneration, with huge implications for translational human endeavors.

项目摘要 该项目的长期目标是探索和验证多刺小鼠Acomys作为一种新的 和独特的模型系统，用于理解分子、细胞和组织水平的机制 修复再生的哺乳动物，并将这一知识转化为发展， 治疗性再生的新概念。Acomys可以再生一系列惊人的 全层皮肤创伤后无瘢痕组织：平滑肌、骨骼肌 肌肉，真皮，头发，腺体;此外，它可以再生软骨后，耳拳;和 在骨骼肌再生、心脏损伤或心肌损伤过程中， 脊髓损伤。我们假设，这种缺乏纤维化反应是一个基本的 这种生物体的细胞的特性，因为胶原蛋白沉积的遗传控制， 其它基质分子已经不同地进化以产生弱皮表型， 在猎物攻击后对该物种的生存有很大的好处。因此，在 改变的胶原纤维化反应允许内源性再生 机制发挥作用。该应用程序的目的是生成一个从头开始的整体 Acomys的基因组序列，这样我们就可以进行比较基因组学， 胶原蛋白和基质沉积的控制，无论是在编码或调节序列， 组织损伤这项工作将使该领域能够研究纤维化和 再生和产生一个基础设施，从适应和发展翻译 人类再生治疗的想法。 相关性 以无疤痕的方式再生复杂组织和器官的能力是 再生医学，但我们目前还没有哺乳动物模型来研究 参与细胞和分子过程。我们发现了一种新的哺乳动物， 小鼠，它可以再生许多组织而不诱导纤维化，在这个提议中，我们 打算揭示这种生物体用于再生机制的遗传控制， 修复性再生，对人类的转化努力产生巨大影响。