COMPARATIVE GENOMIC ANALYSIS OF VERTEBRATE LIMB REGENERATION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这项拟议研究的长期目标是了解脊椎动物肢体再生的分子调控，并将这些信息应用于设计恢复高等脊椎动物（包括人类）肢体再生反应的疗法，这些动物已经失去了这种能力。再生因创伤或疾病而失去的功能性附属物的能力是一个重要的生物医学问题，仅在美国就可能影响190万受影响的人。虽然组织相互作用调节肢体再生已经很好地表征了几十年的研究urodele蝾螈，基本上是唯一的模式生物采用到目前为止，启动和维持再生反应的分子信号才刚刚开始被阐明。进展受到两个关键限制的限制：第一，缺乏多样性的实验模型没有利用比较分析的力量;第二，依赖于肢体模式候选基因的方法没有从根本上告知我们的再生特定的分子和生理信号启动肢体再生的理解。为了解决这些缺点，该项目将实施新的比较分析，包括系统水平的功能基因组方法，以了解在进化上不同的脊椎动物生物，如鲨鱼，冰鞋，和原始淡水鱼类物种再生的细胞和分子基础。采用一种新的比较方法应该揭示脊椎动物肢体/鳍再生的基本机制中意想不到的共性和差异，并深入了解为什么人类等脊椎动物失去了这种能力，这是开发人类创伤性肢体丧失临床疗法的基本步骤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-range goal of this proposed research is to understand the molecular regulation of vertebrate limb regeneration, and apply this information toward designing therapies that restore regenerative responses in the limbs of higher vertebrates (including humans) that have lost this ability. The ability to regrow functional appendages lost to trauma or disease is a significant biomedical problem, potentially impacting 1.9 million afflicted persons in the US alone. While the tissue interactions regulating limb regeneration have been well-characterized over decades of research on urodele salamanders, essentially the only model organisms employed to date, the molecular signals initiating and maintaining regenerative responses are only beginning to be elucidated. Progress has been constrained by two critical limitations: first, the lack of diversity in experimental models has not exploited the power of comparative analyses; second, reliance on limb-patterning candidate gene approaches have not fundamentally informed our understanding of regeneration-specific molecular and physiological signals initiating limb regrowth. To address these shortcomings, this project will implement novel comparative analyses, including systems-level functional genomic approaches, to understand the cellular and molecular basis of regeneration in evolutionarily disparate vertebrate organisms such as sharks, skates, and primitive freshwater fish species. Adopting a novel comparative approach should reveal unexpected commonalities and differences in the basic mechanisms of vertebrate limb/fin regeneration, and yield insight into why amniotes such as humans have lost this ability, which is a fundamental step in developing human clinical therapies for traumatic limb loss.