A comparative approach to evaluate muscle growth in an indeterminate growth model

在不确定生长模型中评估肌肉生长的比较方法

• 批准号: 7928950
• 负责人: PEGGY R BIGA
• 金额: $ 7.18万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-09 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928950
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Atrophic; Biological Markers; Biological Models; Cachexia; Cell Nucleus; Cells; Characteristics; Degenerative Disorder; Disease; Early identification; Exhibits; Fishes; Functional disorder; Genes; Genetic; Genetic Models; Genomics; Goals; Growth; Growth Factor; Hormonal; In Vitro; Injury; Life; Malignant Neoplasms; Mammalian Genetics; Metabolic; Modeling; Molecular; Molecular Target; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Muscular Atrophy; Musculoskeletal Diseases; Myoblasts; Myopathy; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural regeneration; Pathway interactions; Phenotype; Physiological; Physiology; Population; Prevention; Prevention therapy; Property; Protein Isoforms; RNA Splicing; Recruitment Activity; Regulation; Regulatory Pathway; Research; Signal Transduction; Skeleton; Somatotropin; System; Systemic disease; Techniques; Testing; Therapeutic; Trauma; Variant; Wasting Syndrome; Work; age related; cell growth; cell growth regulation; combat; comparative; design; improved; indexing; injured; insight; interest; muscle regeneration; myostatin; new technology; novel; novel therapeutics; protein degradation; public health relevance; repaired; response; response to injury; sarcopenia; satellite cell; skeletal disorder diagnosis; therapy design; wasting

DESCRIPTION (provided by applicant): Project Summary Muscle wasting syndrome and cachexia are associated with many degenerative diseases, like cancer, AIDS, and other systemic diseases. Muscular atrophy is primarily a result of increased protein degradation in the muscle cells. Muscle satellite cells provide nuclei for post-natal growth and are involved in repair and regeneration of muscle tissue following injury or disease. Activation of satellite cells in response to injury is known to occur to aid in muscle regeneration. In severe states of cancer-related cachexia and age-related wasting, muscle regeneration does not appear to be active. It is unclear why satellite cells in these states are not activated, and it is unclear if these cells possess the ability to replenish during severe atrophy. Unlike conventional mammalian models, several fish species, including the giant danio (Danio aequipinnatus), exhibit an interesting growth type, indeterminate growth, which allows them to recruit new developing muscle fibers from satellite cell populations throughout their lives. This growth physiology phenotype serves as a powerful comparative model system for understanding the activation and proliferation of satellite cells under several conditions. Therefore, it is the long-term goal of the PI to employ the giant danio as a comparative model organism to investigate molecular, hormonal, and physiological characteristics of satellite cells in determinate and indeterminate growth models following trauma or injury. This proposal begins to address this goal by first characterizing the ability, extent, and target molecular aspects of giant danio satellite cells activation following injury. This proposal will investigate specific regulatory pathways uncharacterized in indeterminate growth regulation and injury response (Specific Aim 1) and to identify novel pathways specific to injury response in indeterminate growth using a global approach (Specific Aim 2). The comparative muscle growth culture system is advantageous for prevention, treatment, and design of new therapeutic techniques for muscle trauma and disease states like cachexia and sarcopenia, as it takes advantage of a 'normal' physiological state in an indeterminate model. This approach will be utilized for the identification of early genetic and/or biological markers for muscle disease and even muscle metabolic dysfunction. Thus, the main objectives of the proposed work are to characterize novel pathways in indeterminate muscle growth regulation to identify target pathways of satellite cell activation in indeterminate growth. PUBLIC HEALTH RELEVANCE: Project Narrative Understanding muscle cell growth regulation, regeneration and repair is imperative to developing new preventative and therapeutic strategies for combating muscle wasting syndromes associated with many degenerative diseases. This project is intended to utilize a novel, powerful, comparative muscle growth technique that will allow us to characterize novel pathways regulating muscle cell regeneration by taking advantage of a genetic model exhibiting indeterminate growth. This comparative approach will also give new insight into the regulation of continuous muscle growth seen in non-mammalian models that can be carried over into the mammalian model to test novel prevention and therapy strategies.

描述（由申请人提供）： 项目摘要肌肉浪费综合征和恶病质与许多退行性疾病有关，例如癌症，艾滋病和其他全身性疾病。肌肉萎缩主要是肌肉细胞中蛋白质降解增加的结果。肌肉卫星细胞为产后生长提供核，并参与受伤或疾病后肌肉组织的修复和再生。已知卫星细胞的激活是有助于肌肉再生的。在严重的与癌症相关的缓存和与年龄有关的浪费的状态中，肌肉再生似乎没有活跃。目前尚不清楚为什么没有激活这些状态的卫星细胞，并且尚不清楚这些细胞是否具有在严重萎缩期间补充的能力。与传统的哺乳动物模型不同，包括巨型Danio（Danio Aequipinnatus）在内的几种鱼类表现出有趣的生长类型，不确定的生长，这使他们能够在整个生命中招募从卫星细胞种群中招募新的发育中的肌肉纤维。这种生长生理表型是一种强大的比较模型系统，可在几种条件下理解卫星细胞的激活和增殖。因此，PI的长期目标是利用巨型Danio作为比较模型的生物体来研究卫星细胞在创伤或损伤后确定和不确定的生长模型中卫星细胞的分子，激素和生理特征。该建议开始通过首先表征巨型Danio卫星细胞在受伤后激活的能力，程度和目标分子方面开始解决这一目标。该建议将研究在不确定的生长调节和损伤反应中未表征的特定调节途径（特定目标1），并使用全球方法确定对不确定生长中损伤反应的新途径（特定的目标2）。比较肌肉生长培养系统有利于预防，治疗和设计针对肌肉创伤的新治疗技术和疾病状态（如卡希克西和肌肉减少症），因为它利用了不确定模型中的“正常”生理状态。这种方法将用于鉴定肌肉疾病甚至肌肉代谢功能障碍的早期遗传和/或生物标记。因此，所提出的工作的主要目标是表征不确定的肌肉生长调节中的新途径，以鉴定不确定生长中卫星细胞激活的靶途径。 公共卫生相关性： 理解肌肉细胞生长，再生和修复的项目叙事对于制定与许多退化性疾病相关的肌肉浪费综合症打击肌肉浪费综合症至关重要。该项目旨在利用一种新颖，功能强大的比较肌肉生长技术，这将使我们能够通过利用表现出不确定生长的遗传模型来表征调节肌肉细胞再生的新型途径。这种比较方法还将为在非哺乳动物模型中看到的连续肌肉生长的调节提供新的见解，这些模型可以将其转移到哺乳动物模型中，以测试新的预防和治疗策略。