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Mechanisms of skeletal patterning during limb development and regeneration

肢体发育和再生过程中骨骼模式的机制

基本信息

批准号：
9913278
负责人：
James R Monaghan
金额：
$ 35.62万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9913278
关键词：
Adopted Affect Agonist Ambystoma Ambystoma mexicanum Amputation Animals Back Biology Birth CRISPR/Cas technology Cell surface Cells Child Congenital Abnormality Connective Tissue Cells Deformity Disease Distal Engineering Epigenetic Process Event Fluorescent in Situ Hybridization Future Gene Expression Genes Genetic Genetic Transcription Genomic approach Goals Grant Human Individual Knowledge Laboratories Ligands Limb Development Limb structure Mediating Medicine Memory Modification Molecular Molecular Target Natural regeneration Outcome Pattern Pharmacology Play Process Prosthesis Regenerative Medicine Resolution Retinoic Acid Receptor Role Salamander Signal Transduction Signaling Molecule Site Structure System Testing Therapeutic Tissues Trauma Tretinoin United States blastema chondrodysplasia clinically relevant disability epithelial wound in vivo injured insight knockout gene limb regeneration morphogens predictive modeling predictive test progenitor receptor regenerative regenerative therapy retinoic acid receptor alpha retinoic acid receptor gamma single-cell RNA sequencing skeletal skeletal disorder skeletal regeneration therapeutic target transcriptomics

项目摘要

PROJECT SUMMARY Limb congenital defects are among the most common causes of disability in the United States affecting 0.8/1000 children born each year. Recent realizations of plausible regenerative medicine therapies in humans has increased efforts towards understanding examples of animal regeneration and the mechanisms that drive the process. In this proposal, we aim to provide insight into the mechanisms that facilitate regeneration by studying a clinically relevant signaling molecule, retinoic acid, during limb regeneration in the salamander. Axolotl salamanders (Ambystoma mexicanum) are particularly useful, because they regenerate entire limbs after amputation by generating a heterogeneous mass of lineage- restricted progenitors called a blastema at the amputation site. The blastema uses positional information retained in connective tissue cells to regenerate the proper limb regions. The goal of this proposal is to the endogenous role in this process and study how positional information is established and maintained in connective tissue cells, which is critical to our understanding of limb regeneration. We will use unbiased single cell RNAseq and spatial transcriptomic approaches to compare gene expression at single-cell resolution throughout the regeneration process. We will also determine the transcriptional targets of retinoic acid specifically in limb connective tissue cells that are undergoing reprogramming from distal to proximal cell identity. Lastly, the positional memory of connective tissue cells will be experimentally programmed in vivo to demonstrate how positional memory is maintained. In the end, the major outcome of this project will be to know how a salamander limb knows what limb structures to grow back in order to stimulate new regenerative approaches in mammalian systems.

项目摘要肢体先天性缺陷是美国残疾的最常见原因之一， 0.8/1000新生儿最近实现的合理再生医学疗法，人类越来越努力地了解动物再生的例子，推动这一进程的机制。在本提案中，我们的目标是深入了解这些机制通过研究一种临床相关的信号分子，视黄酸，蝾螈的再生蝾螈（Ambystoma mexicanum）是特别有用的，因为他们在截肢后通过产生异质的血统来再生整个肢体- 被称为芽基的限制性祖细胞。芽基使用位置性的这些信息保留在结缔组织细胞中，以再生适当的肢体区域。这个目标本文的建议是对这一过程中的内源性作用进行研究，并研究位置信息是如何建立的并维持在结缔组织细胞中，这对我们理解肢体再生至关重要。我们将使用无偏的单细胞RNAseq和空间转录组学方法来比较基因组。在整个再生过程中以单细胞分辨率表达。我们还将确定视黄酸的转录靶点，特别是在肢体结缔组织细胞中，从远端到近端细胞身份的重编程。最后，结缔组织的位置记忆将在体内对细胞进行实验编程，以证明位置记忆是如何维持的。最后，这个项目的主要成果将是了解蝾螈的肢体是如何知道什么肢体结构重新生长，以刺激哺乳动物系统中新的再生方法。