Muscle Stem Cell Lineage

肌肉干细胞谱系

• 批准号: 8664811
• 负责人: CHEN-MING FAN
• 金额: $ 33.02万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664811
• 关键词: 2 year old; Acute; Adipocytes; Adult; Age; Aging; Alleles; Biology; Cell Lineage; Cell model; Cells; Data; Dermomyotome; Development; Embryo; Embryonic Development; Exercise; Fibroblasts; Fibrosis; Genes; Genetic; Genetic Recombination; Growth; Homeostasis; In Vitro; Injury; Knock-in Mouse; Knowledge; Locomotion; Longevity; Mechanics; Movement; Mus; Muscle; Muscle satellite cell; Muscular Dystrophies; Natural regeneration; Posture; Reporter; Research; Research Design; Role; Serum; Skeletal Muscle; Somites; Stem cells; System; Tamoxifen; Testing; Therapeutic; Toxin; aged; blastomere structure; cell type; design; fusion gene; homeodomain; in vivo; mouse model; muscle aging; muscle hypertrophy; muscle regeneration; progenitor; regenerative; research study; satellite cell; self-renewal; stem cell population; tool; transcription factor; young adult

DESCRIPTION (provided by applicant): The mammalian musculature provides mechanical force for locomotion. This system undergoes remodeling throughout lifetime and displays remarkable ability to regenerate from reservoirs of muscle stem cells. However, the muscle regenerative capacity declines with age. This proposal focuses on defining the origin(s) and roles of muscle stem cells during the life span of a mouse. We propose to use a knock-in allele replacing Pax7 with the Cre-ERT2 fusion gene (the Pax7CE allele) for tamoxifen (tmx) inducible cell lineage tracing in following aims: Aim 1: Pax7 lineage during embryogenesis: We will use the Pax7CE allele to determine: 1) When and where do Pax7+ embryonic cells become fate-restricted to the muscle lineage? 2) When do Pax7+ embryonic cells take on a satellite cell fate? 3) Do embryonically derived Pax7 descendant cells give rise to adult satellite cells capable of muscle regeneration? Aim 2: Pax7 lineage in adult muscles: We will further ask: 1) After forced exercise, do Pax7+ cells become activated and fuse into existing myofibers? 2) When Pax7+ cells are genetically ablated by diptheria toxin (DTA) in adulthood, can muscle maintain homeostasis in mass and/or regenerate after acute injury? Aim 3: Pax7 lineage in aged muscles: Aged (> 2 year old for a mouse) muscles are poor in regeneration and accumulate fibrosis and adipocytes. We design experiments to ask: 1) How quiescent are adult satellite cells? 2) Are aged satellite cells a different population of stem cells from those of young adults? 3) Do aged Pax7+ satellite cells trans-fate into fibroblasts or adipocytes after injury?

描述（由申请人提供）：哺乳动物的肌肉为运动提供了机械力。该系统在整个生命周期中都经历了重塑，并且表现出显着的能力从肌肉干细胞的储层中再生。但是，肌肉再生能力随着年龄的增长而下降。该提议着重于在小鼠的寿命中定义肌肉干细胞的起源和作用。 We propose to use a knock-in allele replacing Pax7 with the Cre-ERT2 fusion gene (the Pax7CE allele) for tamoxifen (tmx) inducible cell lineage tracing in following aims: Aim 1: Pax7 lineage during embryogenesis: We will use the Pax7CE allele to determine: 1) When and where do Pax7+ embryonic cells become fate-restricted to the muscle lineage? 2）PAX7+胚胎细胞何时采用卫星细胞命运？ 3）胚胎衍生的PAX7后代细胞是否会产生能够肌肉再生的成年卫星细胞？ AIM 2：成人肌肉中的PAX7谱系：我们将进一步问：1）强迫运动后，PAX7+细胞会被激活并融合到现有的肌纤维中吗？ 2）当Pax7+细胞在成年期被遗传性毒素（DTA）遗传时，肌肉是否可以在急性损伤后保持体内平衡和/或再生？ AIM 3：老年肌肉中的PAX7谱系：老化（小鼠> 2岁）的肌肉在再生和积累纤维化和脂肪细胞方面很差。我们设计实验要问：1）成年卫星细胞的静止如何？ 2）老年卫星细胞是否与年轻人的干细胞不同？ 3）损伤后，老化的PAX7+卫星细胞会转移到成纤维细胞或脂肪细胞中吗？