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Sizing and Scaling in Functional Muscle Cells

功能性肌肉细胞的大小和缩放

基本信息

批准号：
9389959
负责人：
MARY K BAYLIES
金额：
$ 45.93万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9389959
关键词：
Abdomen Aging Alpha Cell Area Atrophic Biological Biological Models Biology Cell Nucleus Cell Size Cell physiology Cells Characteristics Computer Simulation Cues Cytoplasmic Tail DNA Data Development Diploidy Disease Drosophila genus Drosophila melanogaster Embryo Endoplasmic Reticulum Exercise Exhibits Generations Genes Genetic Goals Golgi Apparatus Growth Homeostasis Hypertrophy Imaging Device Individual Intrinsic factor Investigation Length Measurement Measures Mechanics Microtubules Mitochondria Modeling Molecular Mosaicism Muscle Muscle Cells Muscle Development Muscle Fibers Muscle function Muscular Atrophy Myoblasts Myopathy Nature Nuclear Nuclear Import Optics Organelles Organism Pathway interactions Pattern Physiological Play Ploidies Positioning Attribute Process Regenerative Medicine Regulation Regulation of Cell Size Reproducibility Research Role Sarcomeres Shapes Site Stereotyping Synapses System Tendon structure Testing Time Tissues Translating base cell type genetic manipulation imaging approach in vivo in vivo Model insight mathematical model mechanical force muscular structure nerve supply neuromuscular novel relating to nervous system response scale up tool

项目摘要

Project Summary/Abstract Cell size is one of the most basic and defining features of a cell. However, the mechanisms controlling size are poorly understood. This is particularly true for muscle cells, which have a remarkable capacity to increase their size in response to exercise, and to decrease in size upon inactivity, aging, or disease. The long-term goal of this proposal is to define genes, mechanisms, and networks responsible for muscle size scaling under normal, hypertrophic, and atrophic conditions. These mechanisms will translate both to a better understanding of fundamental aspects required to build a functioning muscle and to better strategies for treating muscle atrophy due to aging and disease. The objective of this proposal is to define salient features of the muscle cell that determine muscle size using genetic, cell biological, mathematical modeling and imaging approaches. We will perform these studies in the Drosophila larval musculature, taking advantage of its cellular simplicity, easy readouts for cell function, optical clarity, and the availability of advanced tools for imaging and tissue-specific manipulation of genetic, environmental, and mechanical factors in vivo. In Aim 1, we will acquire and mathematically model measurements of cell and organelle size, particularly of nuclear distribution, size/ploidy, and activity, to determine those that scale with muscle size under normal, hypertrophic and atrophic conditions. We will use this model to predict the importance of specific parameters and interrelationships between these parameters to generate functional muscle sizes. We will test our predictions by genetically manipulating the specific measured parameters. Already we have found novel compensatory mechanisms that are invoked to achieve a functioning muscle cell: nuclear area can be adjusted to account for differences in nuclear numbers in the same sized muscle. In Aim 2, the localized effects of innervation, and the effects of mechanical forces on individual nuclei size and activity and overall cell size, will be investigated. Mechanisms responsible for altering nuclear size and activity will be uncovered. Lastly, Aim 3 will focus on the investigation of Myonuclear Domain sizes in normal, hypertrophic and atrophic muscles. We will also mathematically model and test mechanisms by which Myonuclear domains are created and maintained under normal, hypertrophic and atrophic conditions. Altogether, these experimental and computational approaches will identify defining parameters of muscle cell size under normal, hypertrophic and atrophic conditions, and their physiological range required for muscle function. These data will reveal general principles of cell size regulation, provide insight to how improper regulation of these processes results in disease, and inform regenerative medicine aimed at muscle.

项目总结/文摘