Regulation of synapse formation and function by cholesterol

这项研究调查了胆固醇如何影响大脑中神经细胞之间的通讯。神经细胞通过突触进行交流，突触是两个神经元非常接近的地方。为了通过突触传递信号，一个神经细胞释放称为神经递质的小分子，第二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中的小囊泡中。为了释放神经递质，这些小泡整合到神经细胞膜外部，从而向细胞外部开放。然后，囊泡被迅速从外膜取回，并重新注入神经递质以传递另一种信号。必须严格控制囊泡回收，以确保所有蛋白质都正确地分选到囊泡中。我们感兴趣的是囊泡形成的机制以及胆固醇在这一过程中所起的作用。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上的胆固醇，以及胆固醇如何影响从神经细胞外膜恢复突触小泡的过程。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，并测量对不同突触囊泡形成途径的影响。将对受影响最大的途径进行详细研究，以找出胆固醇代谢的哪些方面调节囊泡的形成。我们还将研究胆固醇如何影响不同成分进入囊泡的包装。更深入地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退化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.