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REGULATION OF SKELETAL MUSCLE DEVELOPMENT AND MAINTENANCE BY PROTEIN O-GLUCOSYLTRANSFERASE 1 (POGLUT1)

蛋白质 O-葡萄糖基转移酶 1 (POGLUT1) 调节骨骼肌发育和维持

基本信息

批准号：
10065324
负责人：
Radbod Darabi
金额：
$ 38.57万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10065324
关键词：
Adult Affect Alleles Animals Biochemical Biological Biological Assay Biology CRISPR/Cas technology Carbohydrates Cell Communication Cell Culture Techniques Cell Surface Proteins Cell model Cells Complex Consensus Sequence Data Defect Development Disease Disease model Drosophila genus Embryonic Development Engraftment Enzymes Epidermal Growth Factor Estrogen receptor positive Family Functional disorder Future Genes Genetic Diseases Glucose Glucosyltransferase Growth Homing Human Immunodeficient Mouse Impairment In Vitro Injury Knock-in Knockout Mice Limb-Girdle Muscular Dystrophies Link Maintenance Mammals Mediating Molecular Mus Muscle Muscle Cells Muscle Development Muscle satellite cell Muscular Dystrophies Mutation Myoblasts Myopathy NOTCH3 gene Notch Signaling Pathway Pathology Pathway interactions Patients Phenotype Physiology Play Polysaccharides Post-Translational Protein Processing Process Proliferating Protein Glycosylation Proteins Proteomics Regulation Reporting Role Siblings Signal Transduction Site Skeletal Muscle Structure Techniques Testing Therapeutic Transgenes base body system c new causal variant cell type conditional knockout consanguineous family experimental study fly glycosylation glycosyltransferase human disease in vivo induced pluripotent stem cell insight migration mouse genetics muscle form mutant myogenesis notch protein novel novel therapeutic intervention postnatal progenitor receptor repaired response satellite cell self-renewal skeletal stem cells therapeutic target

项目摘要

SUMMARY Carbohydrate addition (glycosylation) is one of the most common posttranslational modifications of secreted and cell surface proteins. Glycosylation is critical for normal animal development and physiology, and mutations in genes involved in glycosylation cause more than a 100 human diseases with diverse phenotypes. However, glycan structures are complex, and each form of glycosylation can be found in tens to thousands of target proteins. Accordingly, understanding the molecular mechanisms underlying glycosylation disorders constitute a major challenge. One of the critical roles played by protein glycosylation is the regulation of a cell-to-cell communication mechanism called the Notch signaling pathway. Notch signaling regulates many processes during animal development and adult maintenance. For example, studies in mice and cell culture have shown that muscle development and muscle repair after injury depend on Notch signaling in mammals. However, mutations in Notch pathway components or modulators have not been reported in human patients with muscular dystrophy. We have recently reported a consanguineous family in which several siblings suffer from LGMD-2Z, which is a new form of limb-girdle muscular dystrophy. LGMD-2Z is caused by homozygosity for a recessive mutation in a gene called POGLUT1. POGLUT1 is a glycosyltransferase which adds O-linked glucose to a number of transmembrane and secreted proteins, including multiple components of the Notch signaling pathway. We have previously shown that POGLUT1 regulates Notch signaling in fruit flies and mice. Analysis of the muscle tissues and myoblasts isolated from the above-mentioned patients provided evidence suggesting that impaired Notch signaling plays an important role in the pathophysiology of this form of muscular dystrophy. However, the biologically-relevant targets of POGLUT1 in the Notch pathway and other pathways in the muscle are not known. In this proposal, we will use biochemical and cell culture assays, proteomic profiling, mouse genetic experiments and iPS cell experiments to determine the molecular mechanisms underlying the regulation of muscle development and maintenance by POGLUT1 and to identify its relevant targets. We will use iPS cells from patients, along with a CRISPR/Cas9-mediated corrected version of them, for in vitro disease modeling and in vivo engraftment experiments. These studies have the potential to provide novel insight into the pathophysiology of a muscular dystrophy caused by abnormal glycosylation and might establish a new framework for future therapeutic approaches for muscle diseases.

总结