Towards an understanding of the molecular mechanisms that underlie the function of vascular ATP-sensitive potassium (KATP) channels

高血压是导致中风和心脏病的危险因素，数十亿人正遭受这些疾病的折磨。血压是由血液流经全身的动脉直径来调节的。这些血管的直径受到周围平滑肌细胞层的积极控制。血管平滑肌收缩使动脉直径变窄，血压升高。相反，它的松弛会降低血压。在动脉的内壁是一层内皮细胞，它调节平滑肌的功能。血管平滑肌细胞收缩/舒张过程的重要调节因子之一是一类被称为离子通道的蛋白质，离子通道是允许离子（如钾）进出细胞的微小门控孔。atp敏感钾（KATP）通道在调节心血管系统功能中起着特别重要的作用。这些通道的一个关键特征是它们的开启和关闭受细胞代谢状态变化的调节。这是因为它们受到细胞内ATP浓度的调节，ATP分子是细胞的能量货币。在心脏中，KATP通道在心脏压力时特别活跃，例如当血流受损（缺血）时，它们有助于防止心脏病发作。然而，在平滑肌中，它们在调节血管张力的静息水平，从而调节血管直径方面很重要。当这些毛孔打开时，血管平滑肌细胞放松，降低血压；当它们闭合时，有利于收缩，血压升高。缺乏KATP通道的小鼠可能死于一种被称为Prinzmetal综合征的冠状血管痉挛，这种疾病在人类中也有发现。因此，了解KATP通道的打开和关闭是如何被调节的是非常重要的。我的研究目的是确定血管KATP通道功能的分子机制，阐明这些通道如何受到细胞能量代谢的调节，并探索KATP通道基因突变如何导致血管疾病。我将使用一些实验技术来解决这些问题：从测量离子通过单个离子通道到对KATP通道进行基因修饰。我还将探讨药物如何调节血管KATP通道。这样的研究将使我们更好地了解这个通道在正常条件下是如何运作的，以及在疾病状态下是什么出了问题。它们还可能促进治疗高血压和心绞痛等心血管疾病的新药的开发。

High blood pressure is a risk factor for stroke and heart disease from which billions of people are suffering. Blood pressure is regulated by the diameter of the arteries through which the blood flows around the body. The diameter of these vessels is actively controlled by a surrounding layer of smooth muscle cells. Contraction of vascular smooth muscle narrows the arterial diameter and increases blood pressure. Conversely, its relaxation lowers blood pressure. On the inner wall of the artery is a layer of endothelial cells that regulate the function of smooth muscle. One of the important regulators of the contraction/relaxation process in vascular smooth muscle cells is a class of proteins known as ion channels, tiny gated pores that allow ions (such as potassium) to move into and out of the cell. The ATP-sensitive potassium (KATP) channels play a particularly important role in regulating the function of the cardiovascular system. A key feature of these channels is that their opening and closing is regulated by changes in the metabolic state of the cell. This is because they are modulated by the intracellular concentration of ATP, the molecule that serves as the energy currency of the cell. In the heart, KATP channels are especially active in times of cardiac stress, such as when blood flow is compromised (ischemia), and they help to protect against heart attack. In smooth muscle, however, they are important in regulating the resting level of vessel tone, and thus the diameter of the blood vessel. When these pores are open, vascular smooth muscle cells relax, lowering the blood pressure; when they are closed, contraction is favoured and blood pressure increases. Mice that lack KATP channels can die from a type of coronary vasospasm known as Prinzmetal syndrome that is also found in humans. It is therefore very important to understand how the opening and closing of the KATP channel is regulated. The aim of my studies is to determine the molecular mechanisms that underlie the function of vascular KATP channels, to elucidate how these are regulated by the energy metabolism of the cell, and to explore how mutations in KATP channel genes cause vascular disorders. I will use a number of experimental techniques to address these questions: from measurement of the passage of ions through a single ion channel to genetic modification of the KATP channel. I will also explore how drugs regulate vascular KATP channels. Such studies will provide us with a better understanding of how this channel operates under normal conditions and what goes wrong in disease states. They may also facilitate the development of novel drugs for the treatment of cardiovascular diseases such as hypertension and angina.