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

• 批准号: 9912208
• 负责人: MOHAMMED AKAABOUNE
• 金额: $ 44.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912208
• 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; Estrogen receptor positive; 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; Structure; 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

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.

稳定而有效的突触传递在很大程度上取决于维持一个高水平的 突触部位的突触后受体的数量/密度。于神经肌肉接点 (NMJ)脊髓运动神经元和骨骼肌细胞之间的突触， 调节突触后烟碱乙酰胆碱受体（AChRs）的稳定性。 动物的寿命在很大程度上仍然未知。我们实验室最近的研究表明，αkap，a 在钙/钙调蛋白激酶II α基因内编码的非激酶肌肉锚定蛋白， 在调节烟碱型乙酰胆碱受体（AChRs）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，我们在第一个目标中建议， 探讨α-kap基因敲低对健康神经肌肉发育的影响 突触在第二个目标中，我们提出研究αkap函数增益的影响， 对受损NMJ的成熟和维持的影响， 肌营养不良蛋白糖蛋白复合物（DGC）（α-突触营养蛋白和α-肌营养不良蛋白）的复合物。在 第三个目的，我们建议研究DGC亚单位之间的分子机制联系， 复合物/αkap/去泛素化蛋白酶USP 9 X与小鼠AChR稳定性的关系 缺乏α-syntrophin/α-dystrobrevin和USP 9 X。这些研究的结果将是 与许多神经肌肉疾病相关，其中AChR的数量和密度是 暴露了