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: 8816147
• 负责人: MARK M RICH
• 金额: $ 22.79万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816147
• 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; vesicular release

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.

项目总结（见说明）：项目3总结：在上一个资助期间，我们意外发现囊泡（微型终板电流，MEPC）的自发释放在体内调节小鼠神经肌肉接头（NMJ）可释放囊泡（n）的数量中起着重要作用。在初步研究中，我们发现，在离体NMJ制剂中的MEPC期间，减少乙酰胆碱与乙酰胆碱受体（AChR）的结合在几分钟内触发n的增加。我们的初步数据表明，这是由于肌肉上AChRs开放引发的逆行信号的改变。总之，我们的研究结果表明，有一个连续的逆行信号，从肌肉运作的一分钟一分钟的时间尺度，以调整突触前功能的运动神经元。我们使用的离体制备允许详细研究这种正在进行的信号传导，这是不可能在体内。在这个提议中，我们将使用体内和体外研究来剖析这一途径背后的分子信号。更好地了解这一途径将有助于理解突触可塑性和运动神经元对损伤的反应，包括兴奋性的变化和突触输入的丧失。我们假设，我们正在研究的营养信号通路在NMJ的中断是一个触发器，诱导潜在的适应不良的脊髓可塑性周围神经损伤后。我们的研究结果可能对运动神经元疾病、脊髓性肌萎缩症以及神经肌肉疾病重症肌无力有意义。