Identification of Sulfs as therapeutic targets for the treatment of age-impaired skeletal muscle regeneration

确定磺基作为治疗年龄受损骨骼肌再生的治疗靶点

• 批准号: 8918172
• 负责人: Xingbin Ai
• 金额: $ 32.26万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918172
• 关键词: Abbreviations; Age; Aging; Agonist; Animal Model; Basement membrane; Binding; Biological Assay; Biological Availability; Biological Models; Cell Aging; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Coagulants; Communication; Environment; Enzymes; FGF2 gene; Fibroblast Growth Factor; Fibrosis; Health; Heparin; Heparitin Sulfate; Hepatocyte Growth Factor; Impairment; In Vitro; Individual; Injury; Inorganic Sulfates; Investigation; Knowledge; Lead; Mediating; Mus; Muscle; Mutant Strains Mice; Natural regeneration; Pathway interactions; Phenotype; Population; Prevention therapy; Process; Regulation; Rest; Role; Saline; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal Muscle Satellite Cells; Somatomedins; Structure; Sulfate; Testing; Therapeutic; Transforming Growth Factor beta; age related; aged; base; cell age; effective therapy; environmental change; extracellular; improved; in vivo regeneration; muscle aging; muscle regeneration; myogenesis; receptor; receptor binding; research study; response; satellite cell; small molecule; stem cells; sulfation; therapeutic target; transmission process

DESCRIPTION (provided by applicant): Aging is inevitably associated with diminished regeneration capacity of stem cells. We choose the skeletal muscle as a model system to study mechanisms that regulate the influence from aged environment on stem cell function. Aged skeletal muscle has reduced levels of FGF2 and elevated Wnts and TGF2, leading to decreased proliferation of resident stem cells (so called satellite cells) and increased fibrosis during regeneration. The bioavailability of FGF2, Wnts and TGF2 is regulated by sulfated heparan sulfate. This proposal investigates heparan sulfate-dependent mechanisms that regulate the transmission of age-related environmental signals to satellite cells during skeletal muscle regeneration. The first set of experiments focuses on roles of two extracellular heparan sulfate 6-O-endosulfatases (Sulfs) in differential regulation of the bioavailability of age-related signals. Sulfs enzymatically remodel heparan sulfate 6-O-sulfation, thereby Sulfs reduce Wnts and TGF2 binding to heparan sulfate, while disrupting FGF2 interaction with the receptor. Therefore, Sulfs are hypothesized to promote age-augmented Wnt and TGF2 signaling, while repressing age-reduced FGF2 signaling, leading to impaired function of satellite cells. This hypothesis will be tested by comparing the efficiency of myogenesis, fibrosis and age-related regeneration signaling in aged control, systemic and satellite cell-specific Sulf double mutant mice using a combination of in vivo regeneration and in vitro culture assays. The second set of experiments will test whether heparin, which is similar to heparan sulfate of Sulf-deficient mice in the structure and signaling function, will improve the efficiency of skeletal muscle regeneration in an aged environment. The results of these investigations are expected to lead to the discovery of Sulf- and heparan sulfate-dependent mechanisms that regulate signal communication between satellite cells and the aged muscle environment. Such knowledge may open new venues for prevention and therapy of impaired muscle regeneration by age.

描述（由申请人提供）：衰老不可避免地与干细胞再生能力降低有关。我们选择骨骼肌作为模型系统，以研究调节老化环境对干细胞功能的影响的机制。老化的骨骼肌降低了FGF2水平，WNT和TGF2升高，导致居民干细胞（所谓的卫星细胞）的增殖减少，并增加了再生过程中的纤维化。 FGF2，WNT和TGF2的生物利用度受硫酸盐硫酸盐的调节。该提案研究了硫酸乙酰肝素依赖性机制，这些机制在骨骼肌再生过程中调节与年龄相关的环境信号向卫星细胞的传播。第一组实验的重点是两个细胞外硫酸乙酰肝素6-O-内膜硫酸酯酶（硫）在与年龄相关信号的生物利用度差异调节中的作用。硫酸酶重塑硫酸肝素6-O-硫酸盐，从而降低Wnts并与TGF2结合与硫酸乙酰肝素的结合，同时破坏FGF2与受体的相互作用。因此，假设硫酸可以促进年龄增强的Wnt和TGF2信号传导，同时抑制年龄减少的FGF2信号传导，从而导致卫星细胞功能受损。该假设将通过在老年对照，系统和卫星细胞特异性硫双突变小鼠中使用体内再生和体外培养试验的组合比较肌发生，纤维化和与年龄相关的再生信号传导的效率。第二组实验将测试肝素在结构和信号功能中类似于缺乏硫的小鼠的硫酸乙酰肝素，会提高老化环境中骨骼肌再生的效率。这些研究的结果预计会导致发现硫酸盐和乙酰肝素依赖性机制，这些机制调节卫星细胞与老化的肌肉环境之间的信号通信。这些知识可能会为预防和治疗肌肉再生而开放新的场所。

项目成果

A Shh/miR-206/BDNF cascade coordinates innervation and formation of airway smooth muscle.

• DOI: 10.1523/jneurosci.2745-11.2011
• 发表时间: 2011-10-26
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Radzikinas K;Aven L;Jiang Z;Tran T;Paez-Cortez J;Boppidi K;Lu J;Fine A;Ai X
• 通讯作者: Ai X