The effect of muscle-specific anchoring protein on the biology of the Neuromuscular system

肌肉特异性锚定蛋白对神经肌肉系统生物学的影响

基本信息

批准号：
10365954
负责人：
MOHAMMED AKAABOUNE
金额：
$ 44.01万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365954
关键词：
Adult Affect Animals Biological Models Biology Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cell surface Cells Cholinergic Receptors Complex Data Development Dose Dystrophin Endocytosis Excision Exocytosis Genes Glycoproteins Goals Impairment In Vitro Knock-out Life Link Maintenance Metabolic Modeling Molecular Motor Neurons Mus Muscle Muscle Cells Muscle Fibers Mutant Strains Mice Neuromuscular Diseases Neuromuscular Junction Nicotinic Receptors Outcome Study Pathway interactions Peptide Hydrolases Phenotype Play Postsynaptic Membrane Process Proteins Role Scaffolding Protein Shapes Site Skeletal Muscle Spinal Synapses Synaptic Transmission System Testing Time Transcript Ubiquitin Work alpha synuclein alpha-dystrobrevin density dystrobrevin gain of function in vivo Model knock-down loss of function multicatalytic endopeptidase complex nervous system disorder neuromuscular neuromuscular system novel strategies overexpression postnatal period postsynaptic protein complex receptor receptor density small hairpin RNA synaptic pruning synaptogenesis syntrophin syntrophin alpha1 trafficking young adult

项目摘要

Stable and efficient synaptic transmission depends largely on the maintenance of a high number/density of postsynaptic receptors at synaptic sites. At the neuromuscular junction (NMJ), the synapse between spinal motor neurons and skeletal muscle cells, the mechanisms that regulate the stability of postsynaptic nicotinic acetylcholine receptors (AChRs) over the lifetime of animals remain largely unknown. Recent studies from our lab showed that αkap, a non-kinase muscle anchoring protein encoded within the calcium/calmodulin kinase II α gene, plays an important role in regulating the stability of nicotinic acetylcholine receptors (AChRs) and the structural integrity of the NMJ. In view of these results, we propose in the first aim to investigate the effect of αkap knockdown during the development of healthy neuromuscular synapses. In the second aim we propose to investigate the effect of the gain of function of αkap on the maturation and maintenance of compromised NMJs using mice deficient in the sub- complex of the dystrophin glycoprotein complex (DGC) (α-syntrophin and α-dystrobrevin). In the third aim we propose to investigate the molecular mechanistic link between the DGC sub- complex/αkap/ the deubiquitinating protease USP9X and the stability of AChR stability in mice deficient in α-syntrophin/α-dystrobrevin, and USP9X. The outcomes of these studies will be relevant for many neuromuscular diseases where the number and density of AChRs are compromised.

稳定、高效的突触传递在很大程度上取决于高电位的维持神经肌肉接头处突触后受体的数量/密度。 (NMJ)，脊髓运动神经元和骨骼肌细胞之间的突触，其机制调节突触后烟碱乙酰胆碱受体 (AChR) 的稳定性我们实验室最近的研究表明，αkap 是一种动物的寿命。钙/钙调蛋白激酶 II α 基因内编码的非激酶肌肉锚定蛋白，在调节烟碱乙酰胆碱受体 (AChR) 的稳定性中起重要作用以及 NMJ 的结构完整性鉴于这些结果，我们提出第一个目标：研究 αkap 敲低对健康神经肌肉发育的影响在第二个目标中，我们建议研究 αkap 功能增益的影响。使用亚组缺陷小鼠研究受损 NMJ 的成熟和维持肌营养不良蛋白糖蛋白复合物 (DGC)（α-肌营养不良蛋白和 α-dystrobrevin）的复合物。第三个目标我们建议研究 DGC 子之间的分子机制联系复合物/αkap/去泛素化蛋白酶USP9X和小鼠AChR稳定性缺乏 α-syntropin/α-dystrobrevin 和 USP9X 这些研究的结果将是与许多神经肌肉疾病相关，其中 AChR 的数量和密度与妥协了。