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因疾病、受伤或衰老而受到肌肉损失的影响，但目前尚无法治愈任何形式的肌肉退化，这与国家的使命是一致的。关节炎、肌肉骨骼和皮肤疾病研究所，因此了解肌肉至关重要库珀实验室在最广泛的背景下发现了自然发生的发育和退化。双足沙漠啮齿动物（小埃及跳鼠）发育过程中的肌肉损失。这个过程在动物出生后早期和迅速发生，违背了基于数十年肌肉的预测对传统模式生物的研究，并强调当前理解状态的差距。最令人惊讶的是，尽管肌肉结构蛋白表达迅速且完全丧失，但没有跳鼠足部肌肉成熟早期阶段的细胞死亡或免疫反应的可检测证据。似乎正常进行，但新生的肌肉结构随后被一种未知的物质分解肌肉祖细胞持续存在到肌肉细胞丧失阶段的后期，但它们还不够。对这种非凡表型的深入了解将改变我们的肌肉。了解肌节分解的细胞和分子机制，并有可能识别新生儿肌肉细胞的意外发育可塑性。具体来说，第一个目标将解决令人困惑的观察结果，即没有任何特征我们将检测到多种细胞死亡机制与广泛而快速的肌肉细胞损失同时发生。应用电穿孔介导的细胞追踪方法来追踪肌肉后肌肉谱系的命运细胞不再能够通过肌肉蛋白的表达来识别。第二个目标将实现 RNA。测序方法来识别肌肉损失开始时展开的细胞和分子过程。每个目标都研究了跳鼠足部肌肉细胞损失的一个方面，该损失可能与人类肌肉相交叉退行性疾病在有机体正常发育的情况下仍会发生。本提案中概述的实验是实现更广泛目标的重要第一步了解后足肌肉丧失的显着解剖学特异性背后的分子机制因为细胞和组织功能的基本原理在不同物种中都是保守的，或者说确实如此。传统的模式生物没有任何价值，对本提案中概述的问题的回答将启发在各种组织和环境中探索细胞生物学的新维度。