Elucidating muscle regeneration defects in fukutin KO mice

描述（由申请人提供）：继发性肌营养不良蛋白聚糖病是由蛋白质肌营养不良蛋白聚糖的糖基化（添加糖的过程）失败引起的肌营养不良症的一种形式。肌营养不良聚糖位于细胞表面，当它被适当糖基化时，它在细胞表面与细胞外基质蛋白紧密结合，形成重要的结构和功能。 从细胞外到细胞内的信号联系。在继发性肌营养不良蛋白聚糖病中，细胞外的肌营养不良蛋白聚糖连接被破坏，导致进行性肌无力和消耗以及可能的心脏、大脑和眼睛疾病。营养不良性肌营养不良症包括从新生儿发病的严重疾病伴早死到迟发性疾病（青少年）伴较轻症状的广泛疾病表型。编码fuklavin的基因FKTN突变导致最常见的严重形式的肌营养不良症（福山先天性肌营养不良症）。使用一种新的小鼠模型fukutin-dystroglycanopathy，它最近已被证明，在肌肉发育，再生和分化过程中的dystroglycan异常所需的严重肌营养不良症的小鼠。拟议的研究旨在解决发育或发育后肌营养不良蛋白聚糖功能丧失后肌肉再生的缺陷。本研究的目的是利用fukutin-dystroglycanopathy小鼠模型，探讨dystroglycan功能在肌肉再生缺陷的时间和细胞来源中的作用。为了实现这些目标，提出的具体目标使用遗传学，组织学，生物化学和成像方法来跟踪肌肉损伤后的肌纤维再生。这项研究与人类健康直接相关，因为肌肉再生异常是开发治疗方法以改善肌营养不良症患者生活的关键目标。目前，没有治疗肌营养不良症的方法，因此，预期的研究进展是必要的，并与NIH的使命相关。

DESCRIPTION (provided by applicant): Secondary dystroglycanopathies are a form of muscular dystrophy caused by a failure in the glycosylation (a process of adding sugars) of the protein dystroglycan. Dystroglycan is located at the surface of cells where it tightly binds to extracellular matrix proteins when it is properly glycosylated, forming an important structural and signaling link from the outside to the inside of cells. In secondary dystroglycanopathies, the dystroglycan link outside of cells is disrupted, causing progressive muscle weakness and wasting and possible heart, brain and eye disease. Dystroglycanopathy muscular dystrophies encompass a wide spectrum of disease phenotypes ranging from neonatal onset of severe disease with early death, to late onset disease (teens) with milder symptoms. Mutations in the gene encoding fukutin, FKTN, cause the most common severe form of dystroglycanopathy (Fukuyama congenital muscular dystrophy). Using a novel mouse model of fukutin-dystroglycanopathy, it has recently been shown that dystroglycan abnormalities during muscle development, regeneration and differentiation are required for severe muscular dystrophy in mice. The proposed research aims to address the defects in muscle regeneration following developmental or post-development loss of dystroglycan function. The objectives of the proposed research are to address the role of dystroglycan function in the timing and cell source of muscle regeneration defects using the fukutin-dystroglycanopathy mouse model. To meet these objectives, the proposed specific aims use genetic, histological, biochemical, and imaging methods to track muscle fiber regrowth following muscle injury. This research is directly relevant to human health because abnormalities in muscle regeneration are a key target for developing therapeutics to improve the lives of dystroglycanopathy muscular dystrophy patients. Currently, there is no therapy for dystroglycanopathy muscular dystrophy; therefore, the expected research advances are necessary and relevant to the mission of the NIH.