RETROGRADE TROPHIC SIGNALING THROUGH ACETYLCHOLINE RECEPTORS AT THE NEUROMUSCULA

通过神经肌肉乙酰胆碱受体的逆行营养信号传导

• 批准号: 8627654
• 负责人: MARK M RICH
• 金额: $ 22.57万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8627654
• 关键词: Accounting; Acetylcholine; Acute; Atropine; Axotomy; Basic Science; Binding; Cholinergic Receptors; Chronic; Data; Diffuse; Disease; Grant; Injury; Instruction; Interruption; Knockout Mice; Location; Molecular; Motor Neurons; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Muscle; Myasthenia Gravis; Nature; Nerve; Nervous system structure; Neuromuscular Diseases; Neuromuscular Junction; Nicotinic Receptors; Nitric Oxide; Nitric Oxide Synthase Type I; Pathway interactions; Peripheral nerve injury; Play; Preparation; Process; Property; Receptor Signaling; Recovery of Function; Recurrence; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Spinal Cord; Spinal Cord Plasticity; Spinal Muscular Atrophy; Synapses; Synaptic Cleft; Synaptic plasticity; Testing; Time; Toxin; Transgenic Mice; Vesicle; Work; in vivo; injury and repair; nerve injury; postsynaptic; presynaptic; prevent; response; response to injury; synaptic function

PROJECT SUMMARY (See Instructions): Summary for Project 3: During the previous grant period we made the unexpected finding that spontaneous release of vesicles (miniature endplate currents, MEPCs) plays an important role in regulating the number of releasable vesicles (n) at the mouse neuromuscular junction (NMJ) in vivo. During preliminary studies we found that reducing the binding of acetylcholine to acetylcholine receptors (AChRs) during MEPCs in an ex vivo NMJ preparation triggers an increase in n within minutes. Our preliminary data suggests this is due to alteration of a retrograde signal initiated by opening of AChRs on muscle. Taken together our findings suggest there is a continuous retrograde signal from muscle that operates on a minute by minute time scale to adjust presynaptic function of the motoneuron. Our use of an ex vivo preparation allows for detailed study of this ongoing signaling that is not possible in vivo. In this proposal we will use both in vivo and ex vivo studies to dissect the molecular signaling underlying this pathway. A better understanding of this pathway will have implications for understanding synaptic plasticity and the response of motoneurons to injury including changes in excitability and loss of synaptic inputs. We hypothesize that disruption of the trophic signaling pathway we are studying at the NMJ is a trigger that induces potentially maladaptive spinal cord plasticity following peripheral nerve injury. Our findings could have implications for the motoneuron disease spinal muscular atrophy as well as the neuromuscular disease myasthenia gravis.

项目摘要（请参阅说明）：项目3的摘要：在上一个赠款期间，我们提出了一个意外的发现，即囊泡的自发释放（微型终板电流，MEPC，MEPC）在调节小鼠神经肌肉骨肌的可释放囊泡（N）InVivo中起重要作用。在初步研究中，我们发现在MEPC中减少乙酰胆碱与乙酰胆碱受体（ACHR）的结合，在体内NMJ制备中的结合会在几分钟内触发N的增加。我们的初步数据表明，这是由于通过在肌肉上打开ACHR引发的逆行信号的改变。综上所述，我们的发现表明，肌肉有一个连续的逆行信号，该信号以一分钟的时间尺度运行，以调节运动神经元的突触前功能。我们对离体制备的使用允许详细研究这种正在进行的信号，这种信号在体内不可能。在此提案中，我们将使用体内和体内研究来剖析该途径的分子信号传导。更好地理解该途径将对理解突触可塑性以及运动神经元对损伤的反应具有影响，包括兴奋性和突触输入的丧失。我们假设我们在NMJ上研究的营养信号传导途径的破坏是一种触发因素，可在周围神经损伤后诱导潜在的适应不良的脊髓可塑性。我们的发现可能对运动神经元疾病的脊髓肌肉萎缩以及神经肌肉疾病肌无力肌无力有影响。