Regulation of synapse formation and function by cholesterol

这项提议调查了胆固醇如何影响大脑中神经细胞之间的交流。神经细胞通过突触交流，突触是两个神经元彼此非常接近的地方。为了在突触间传递信号，一个神经细胞释放一种叫做神经递质的小分子，另一个神经细胞感知这些神经递质并做出反应。神经递质储存在突触的小泡中。为了释放神经递质，这些囊泡与外神经细胞膜结合，从而向细胞外开放。然后囊泡迅速从外膜中取出，并重新填充神经递质以传递另一种信号。囊泡回收必须严格控制，以确保所有的蛋白质被正确地分类到囊泡中。我们对囊泡形成的机制和胆固醇在这一过程中所起的作用很感兴趣。神经细胞膜和囊泡含有高水平的胆固醇，这会影响膜的流动性和形状，以及膜蛋白的功能。我们的目标是找出神经细胞如何调节其膜内的胆固醇，以及胆固醇如何影响突触囊泡从外神经细胞膜的回收。为了解决这些问题，我们将培养分离的神经元，诱导其胆固醇代谢的变化，并测量对突触囊泡形成不同途径的影响。我们将详细研究受影响最大的途径，以找出胆固醇代谢的哪些方面调节了囊泡的形成。我们还将研究胆固醇如何影响不同成分进入囊泡的包装。深入了解胆固醇在神经细胞通讯中的作用可能有助于理解神经变性或衰老过程中发生的变化。

This proposal investigates how cholesterol influences the communication between nerve cells in the brain. Nerve cells communicate through synapses, which are sites where two neurons come very close to each other. To transmit a signal across the synapse, one nerve cell releases small molecules called neurotransmitters and the second nerve cell senses these neurotransmitters and responds. Neurotransmitters are stored inside small vesicles in the synapse. To release the neurotransmitter, these vesicles integrate into the outer nerve cell membrane and thus open to the outside of the cell. Vesicles are then quickly retrieved from the outer membrane, and refilled with neurotransmitter to transmit another signal. Vesicle retrieval must be closely regulated to ensure that all proteins are sorted correctly into the vesicle. We are interested in the mechanisms of vesicle formation and in the role that cholesterol plays in this process. Nerve cell membranes and vesicles contain high levels of cholesterol, which influences the fluidity and shape of the membranes, and the function of membrane proteins. We aim to find out how nerve cells regulate cholesterol in their membranes, and how cholesterol affects the retrieval of synaptic vesicles from the outer nerve cell membrane. To address these questions, we will grow isolated neurons, induce changes in their cholesterol metabolism, and measure the effects on different pathways of synaptic vesicle formation. The pathways most affected will be studied in detail to find out what aspects of cholesterol metabolism regulate vesicle formation. We will also investigate how cholesterol might influence the packaging of the different components into the vesicle. Deeper knowledge about the role of cholesterol in nerve cell communication may help to understand changes that occur during neurodegeneration or aging.