Molecular Mechanisms Controlling Homeostatic Cellular Excitability

描述(申请人提供)：动态平衡信号系统在整个生物学中无处不在。根据定义，动态平衡是指细胞或细胞系统对扰动做出反应并保持恒定生理的能力。这一概念已被应用于血压和心率的系统水平控制以及细胞生理系统，包括葡萄糖和细胞内钙的控制4。现在很明显，进化上保守的动态平衡信号系统已经进化到稳定神经和肌肉的兴奋性4。尽管假设控制细胞兴奋的动态平衡信号系统很重要，但人们对其潜在的分子机制知之甚少。在一项大规模的正向遗传筛查中，戴维斯实验室发现了果蝇多重蛋白(DMP)基因的突变，该基因编码一种细胞外基质蛋白，可阻止突触传递的动态平衡调节，称为突触动态平衡。有趣的是，这种细胞外基质蛋白在发育过程中专门调节突触的动态平衡，而不改变突触的形态。因此，它可能作为逆行信号分子，在突触后受体功能受扰时调节突触前神经递质的释放。研究DMP基因的功能将极大地促进我们对突触内稳态的分子机制的了解，这是一个进化上保守的过程，发生在从果蝇到人类的各种生物的NMJ。重要的是，DMP基因具有脊椎动物的同源物，在心肌和神经系统29中表达，潜在地发挥保守的功能，维持神经和肌肉的适当的兴奋性。因此，解开细胞外基质蛋白在突触传递和动态平衡可塑性中的功能， 是开发胶原蛋白相关神经疾病新疗法的关键一步。 与公共健康相关：面对不断变化的输入，神经系统保持恒定的输出：脑细胞的活动太少，破坏了它们的沟通能力；太多 活动导致过度兴奋和癫痫或偏头痛，这些疾病影响着超过10%的人口。一些基因此前已被证明参与控制兴奋性和稳定性的细胞过程，但它们如何协同工作仍不清楚。我们打算描述一种存在于苍蝇和人类中的基因。它似乎是连接其他不同信号的细胞间信号。这种基因的特性将为许多治疗神经元过度活动疾病的新疗法打开大门。

DESCRIPTION (provided by applicant): Homeostatic signaling systems are ubiquitous throughout biology. By definition, homeostasis refers to the ability of a cell or system of cells t respond to a perturbation and maintain a constant physiology. This concept has been applied to the system level control of blood pressure and heart rate as well as cellular physiological systems including control of glucose and intracellular calcium4. It is now apparent that evolutionarily conserved homeostatic signaling systems have evolved to stabilize the excitable properties of nerve and muscle4. Despite the hypothesized importance of the homeostatic signaling systems that control cellular excitation, very little is known about the underlying molecular mechanisms. In a large-scale forward genetic screen the Davis laboratory has identified mutations in the Drosophila multiplexin (dmp) gene, encoding an extracellular matrix protein, that blocks the homeostatic regulation of synaptic transmission, termed 'synaptic homeostasis'. Intriguingly, this extracellular matrix protein specifically regulates synaptic homeostasis without changing synapse morphology during development. Thus, it can potentially function as the retrograde signaling molecule that modulates presynaptic neurotransmitter release upon perturbations of postsynaptic receptor function. Studying the function of the dmp gene would significantly advance our knowledge of the molecular mechanisms of synaptic homeostasis, an evolutionarily conserved process that occurs at the NMJ of organisms ranging from Drosophila to humans. Importantly, the dmp gene has vertebrate homologues that are expressed in cardiac muscles and nervous system29, potentially serving a conserved function to maintain the appropriate excitable properties of nerve and muscle. Unraveling the function of extracellular matrix proteins in synaptic transmission and homeostatic plasticity could, therefore, be a critical step in developing new treatments for collagen-related neurological diseases. PUBLIC HEALTH RELEVANCE: Neural systems maintain a constant output in the face of changing inputs: too little activity of brain cells disrupts their ability to communicate; too much activity leads to over-excitation and epilepsy or migraines, diseases which affect over 10% of the population. A few genes have been previously shown to be involved in the cellular processes controlling the excitability and stability, but how they work together remains unknown. We propose to characterize a gene which exists in flies and in humans. It appears to be an inter-cellular signal connecting other disparate signals. The characterization of this gene will open the door to many new treatments for diseases of neuronal over-activity.