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Investigation into establishing morphology during mouse digit tip regeneration, in the context of vertebrate limb development

在脊椎动物肢体发育的背景下研究小鼠指尖再生过程中形态的建立

基本信息

批准号：
9753331
负责人：
Jessica A Lehoczky
金额：
$ 8.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753331
关键词：
3-Dimensional Address Affect Alleles Amphibia Amputation Apical Cells Child Complex Data Digit structure Distal Embryo Epidermal Ridges Epithelium Experimental Models Expression Profiling Future Genes Genetic Human Investigation LacZ Genes Limb Bud Limb Development Limb structure Mammals Mediating Medical Mesenchyme Modeling Molecular Molecular Genetics Morphology Mus Natural regeneration Newts Pathway interactions Pattern Population Population Heterogeneity Primates Process Rana Regenerative Medicine Reporter Research Rodent Role Salamander Signal Pathway Signal Transduction Stem cells Structure Study models System Tissues Tretinoin Vertebrates Zebrafish appendage base blastema differential expression experimental study healing insight limb regeneration member novel recruit regenerative teleost tissue regeneration tool transcriptome transcriptome sequencing translational study wound

项目摘要

PROJECT SUMMARY Among vertebrates, several species are capable of regenerating portions of their limbs upon amputation, including: newts, salamanders, and larval frogs (which can regenerate their entire limbs), many teleosts including zebrafish (which can regenerate portions of their fins), and some rodents and primates (which can regenerate their digit tips). All of these examples of appendage regeneration occur by epimorphic regeneration, a process which relies upon the recruitment, proliferation, and differentiation of a population of progenitor cells, termed the blastema. Despite decades of study, the molecular process by which the blastema gives rise to a perfectly formed regenerate remains enigmatic. Intriguingly, there are many morphological similarities between the processes of epimorphic regeneration and embryonic limb development, supporting the hypothesis that appendage regeneration may be regulated by the same molecular pathways that govern limb development. To address this hypothesis, we utilize the mouse digit tip, as it is a robust experimental model for epimorphic regeneration, in a human-relevant mammalian system with established genetic tools. We aim to interrogate the role of defined genetic molecular pathways necessary for embryonic limb patterning, during mouse digit tip regeneration. In Aim 1, we determine if the genes En1 or Lmx1b are necessary for dorsoventral patterning of the regenerating mouse digit tip, as they both are in the developing limb. In Aim 2, we address the role of retinoic acid signaling in proximodistal patterning during digit tip regeneration, and use a transcriptome approach to more broadly define any proximodistal patterning pathways in common with limb development. Collectively, this proposed research will advance our limited understanding of epimorphic regeneration, specifically, how the blastema is molecularly patterned to give rise to a properly formed regenerate in three axes. Understanding whether this process utilizes defined embryonic pathways, or novel regeneration-specific pathways, will clarify our broad understanding of epimorphic regeneration, and will set the field on a trajectory to dramatically change translational regenerative medicine.

项目概要在脊椎动物中，有几个物种能够在截肢后再生部分肢体，包括：蝾螈、蝾螈和幼蛙（可以再生整个肢体），许多硬骨鱼，包括斑马鱼（可以再生部分鳍）以及一些啮齿动物和灵长类动物（可以再生他们的数字提示）。所有这些附肢再生的例子都是通过外态再生发生的，这是一个过程它依赖于祖细胞群的招募、增殖和分化，称为胚芽。尽管经过了数十年的研究，胚芽产生完美形成的分子过程再生仍然是个谜。有趣的是，这些过程之间有许多形态上的相似之处。外态再生和胚胎肢体发育，支持附肢的假设再生可能受到与控制肢体发育相同的分子途径的调节。为了解决这个问题假设，我们利用小鼠指尖，因为它是外貌再生的稳健实验模型，具有已建立的遗传工具的与人类相关的哺乳动物系统。我们的目标是质疑定义的角色在小鼠指尖再生过程中，胚胎肢体模式所需的遗传分子途径。瞄准 1，我们确定基因En1或Lmx1b对于再生小鼠的背腹模式是否是必需的指尖，因为它们都处于发育中的肢体中。在目标 2 中，我们讨论了视黄酸信号传导在指尖再生过程中的近远端模式，并使用转录组方法更广泛地定义任何与肢体发育相同的近远模式通路。总的来说，这项拟议的研究将增进我们对外胚再生的有限理解，特别是胚基如何在分子上图案化以在三个轴上产生正确形成的再生。了解此过程是否利用定义的胚胎途径，或新的再生特异性途径，将澄清我们对外貌再生，并将使该领域走上一条显着改变平移再生的轨道药品。