Molecular Mechanisms Controlling Homeostatic Cellular Excitability

控制稳态细胞兴奋性的分子机制

• 批准号: 8454908
• 负责人: Tingting Wang
• 金额: $ 5.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454908
• 关键词: Affect; Biological Assay; Biology; Calcium; Cell physiology; Cells; Collagen; Data; Development; Disease; Drosophila genus; Electrophysiology (science); Epilepsy; Exhibits; Extracellular Domain; Extracellular Matrix; Extracellular Matrix Proteins; Genes; Genetic Screening; Genetic screening method; Heart Rate; Homeostasis; Homologous Gene; Human; Knowledge; Laboratories; Migraine; Molecular; Morphology; Muscle; Mutation; Myocardium; N-terminal; Nerve; Nervous system structure; Neurons; Organism; Output; Physiological; Physiology; Population; Process; Property; Proteins; Regulation; Severities; Signal Transduction; Signaling Molecule; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Vesicle; Work; base; blood glucose regulation; blood pressure regulation; brain cell; chemical genetics; fly; mutant; nervous system disorder; neuromuscular; neurotransmitter release; postsynaptic; presynaptic; receptor function; relating to nervous system; research study; synaptogenesis; transmission process; voltage

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.

描述（由申请人提供）：稳态信号系统在整个生物学中普遍存在。根据定义，稳态是指细胞或细胞系统对扰动做出反应并维持恒定生理的能力。这一概念已被应用于血压和心率的系统级控制以及包括葡萄糖和细胞内钙控制的细胞生理系统4。现在很明显，进化上保守的稳态信号系统已经进化到稳定神经和肌肉的兴奋特性。尽管控制细胞兴奋的稳态信号系统的假设的重要性，很少有人知道有关的分子机制。在一项大规模的正向遗传筛选中，戴维斯实验室已经确定了果蝇多路蛋白（dmp）基因的突变，该基因编码一种细胞外基质蛋白，可阻断突触传递的稳态调节，称为“突触稳态”。有趣的是，这种细胞外基质蛋白特异性调节突触稳态，而不会改变发育过程中的突触形态。因此，它可以潜在地作为逆行信号分子，在突触后受体功能扰动时调节突触前神经递质释放。研究dmp基因的功能将大大提高我们对突触稳态的分子机制的认识，突触稳态是一个进化上保守的过程，发生在从果蝇到人类的生物体的NMJ。重要的是，dmp基因有脊椎动物的同源物，在心肌和神经系统中表达，潜在地提供保守的功能以维持神经和肌肉的适当的可兴奋特性。因此，揭示细胞外基质蛋白在突触传递和稳态可塑性中的功能， 是开发胶原蛋白相关神经疾病新疗法的关键一步。 公共卫生相关性：神经系统在面对不断变化的输入时保持恒定的输出：脑细胞的活动太少会破坏它们的交流能力;太多会破坏它们的交流能力。 活动导致过度兴奋和癫痫或偏头痛，这些疾病影响超过10%的人口。一些基因先前已被证明参与控制兴奋性和稳定性的细胞过程，但它们如何一起工作仍然未知。我们建议描述一种存在于苍蝇和人类中的基因。这似乎是一个细胞间的信号连接其他不同的信号。该基因的特性将为神经元过度活跃疾病的许多新疗法打开大门。