An exploration of the mechanisms of naturally occurring limb muscle loss during neonatal development

新生儿发育过程中自然发生的肢体肌肉丧失机制的探索

基本信息

批准号：
9882964
负责人：
Kimberly Lynn Cooper
金额：
$ 16.69万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9882964
关键词：
Address Aging American Anatomy Animal Model Animals Apoptotic Asses Atrophic Autophagocytosis Biological Models Birth Cell Death Cell Nucleus Cell membrane Cell physiology Cells Cellular biology Characteristics Complement DNA Fragmentation Data Degenerative Disorder Development Dimensions Dipodidae Disease Distal Electroporation Event Foundations Functional disorder Gene Activation Gene Expression Goals Hindlimb Human Immune response Injury Investigation Laboratories Laboratory Animal Models Laboratory mice Limb structure Literature Lysosomes Maintenance Mediating Mission Molecular Mus Muscle Muscle Cells Muscle Development Muscle Proteins Muscle function Muscular Atrophy Myofibrils National Institute of Arthritis and Musculoskeletal and Skin Diseases Natural regeneration Necrosis Neonatal Organism Outcome Pathway interactions Phase Phenotype Process Proteins Research Rodent Sarcomeres Skeletal Muscle Solid Specificity Structural Protein System Testing Time Tissues Transcriptional Activation Ubiquitin Work base cell dimension comparative design developmental plasticity differential expression expectation experimental study foot gene function human disease insight loss of function mouse model multicatalytic endopeptidase complex muscle degeneration muscle form muscular structure myogenesis novel postnatal protein expression repaired skeletal stem cells transcriptome sequencing

项目摘要

Millions of Americans are impacted by muscle loss – as an effect of disease, injury, or aging – and yet there is currently no cure for any form of muscle degeneration. Consistent with the mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, it is therefore essential to understand muscle development and degeneration in the broadest context. The Cooper lab has identified naturally occurring muscle loss during development of a bipedal desert rodent, the lesser Egyptian jerboa. Aspects of the cellular process, which occurs early and rapidly after birth of the animal, defy predictions based on decades of muscle research in traditional model organisms and highlight gaps in the current state of understanding. Most surprising, despite the rapid and complete loss of muscle structural protein expression, there is no detectable evidence of cell death or an immune response in the jerboa foot. Early stages of muscle maturation appear to proceed normally, but nascent muscle structure subsequently disassembles by an as yet unknown mechanism. Muscle progenitor cells persist until late in the phase of muscle cell loss, but they are insufficient to restore muscle. A deep understanding of this remarkable phenotype stands to transform our understanding of the cellular and molecular mechanisms of sarcomere disassembly and to potentially identify unexpected developmental plasticity of neonatal muscle cells. Specifically, the First Aim will address the perplexing observation that no characteristic features of multiple mechanisms of cell death are detected concurrent with widespread and rapid muscle cell loss. We will apply an electroporation-mediated cell tracking approach to follow the fate of the muscle lineage after muscle cells can no longer be identified by expression of muscle proteins. The Second Aim will implement an RNA sequencing approach to identify the cellular and molecular processes unfolding at the initiation of muscle loss. Each Aim investigates an aspect of jerboa foot muscle cell loss that potentially intersects with human muscle degenerative disorders yet here occurs in the context of normal development of the organism. The experiments outlined in this proposal are essential first steps toward a broader goal of understanding the molecular mechanisms that underlie the striking anatomic specificity of hindfoot muscle loss in the jerboa. Since the fundamentals of cell and tissue function are conserved across species, or indeed traditional model organisms would have no value, answers to the questions outlined in this proposal will inspire explorations of new dimensions of cell biology in a variety of tissues and contexts.

数以百万计的美国人受到肌肉损失的影响 - 是疾病，伤害或衰老的影响 - 但目前无法治愈任何形式的肌肉变性。与国家任务一致关节炎和肌肉骨骼和皮肤疾病研究所，因此必须了解肌肉在最广泛的背景下发展和退化。库珀实验室已经确定自然发生在埃及小耶尔巴（Jerboa）的两足动物沙漠啮齿动物发育过程中的肌肉损失。细胞的各个方面动物出生后早期和迅速发生的过程反对基于数十年的肌肉的预测在传统模型生物体中进行研究，并突出当前理解状态的差距。最令人惊讶的是，肌肉结构蛋白表达的快速而完全丧失，没有可检测的细胞死亡证据或Jerboa脚的免疫反应。肌肉成熟的早期阶段似乎正常进行，但新生的肌肉结构随后被一个尚不清楚的机制。肌肉祖细胞持续到肌肉细胞损失阶段的后期，但它们不足恢复肌肉。对这种非凡的表型的深刻理解代表着我们的了解肌节拆卸的细胞和分子机制，并有潜在地确定新生儿肌肉细胞的意外发育塑性。具体而言，第一个目标将解决令人困惑的观察，没有特征的特征发现细胞死亡的多种机制与宽度和快速肌肉细胞丧失并发。我们将应用电穿孔介导的细胞跟踪方法，跟随肌肉后肌肉谱系的命运无法通过表达肌肉蛋白来鉴定细胞。第二个目标将实施RNA 测序方法以识别在肌肉丧失开始时展开的细胞和分子过程。每个目标都调查了Jerboa脚肌肉细胞损失的一个方面，该方面可能与人类肌肉相交退化性疾病却发生在生物体正常发育的背景下。该提案中概述的实验是朝着更广泛目标的重要第一步了解助力肌肉损失引人注目的解剖学特异性的分子机制在Jerboa。由于细胞和组织功能的基本原理在物种之间是保守的，或者确实是传统模型生物没有价值，对本提案中概述的问题的答案将激发在各种组织和环境中对细胞生物学的新维度的探索。