Linking the lipid-sensing TMEM16A channel with lysosomal lipid storage mechanisms: implications for drug discovery

我们依靠电流运行-几乎所有的重要功能，如心脏的跳动，大脑的活动，血管的功能或肌肉收缩都是由通过每个细胞表面（膜）发生的微小电流触发的。负责这些电流的是离子通道，形成微观门控孔的蛋白质，选择性地允许带电离子进出细胞;它们产生的电脉冲启动了生命不可或缺的大量事件，例如上面提到的那些。在体内许多细胞类型中发现的一类离子通道是允许氯离子穿过膜的通道。例如，这些氯离子通道存在于血管的肌肉细胞中。当通道打开时，氯离子“电流”被激活，血管收缩;当通道关闭时，电流被抑制，血管舒张。通过这种方式，血液可以根据需要被引导到身体的各个部位。这个通道的一个特点是它的打开和关闭是由膜本身调节的。膜由油性物质（如胆固醇）组成，组成膜的“油”（技术上称为“脂质”）组成的变化会影响这些氯离子通道的功能，从而影响身体生物学的许多方面。脂质成分本身由其他细胞区室控制，例如溶酶体，它是细胞的专门部分。我们发现，如果溶酶体不能正常工作，氯离子通道也会受到影响。我们现在想确切地了解这是如何发生的，并利用这些新知识来设计新的分子，这些分子最终可以用于控制氯离子通道的功能，并解决许多疾病，如涉及血管的疾病（例如高血压，中风等）。以及脂质含量发生改变的一般疾病（如一种使人衰弱的罕见遗传病，即C型尼曼-皮克病）。为了实现这一雄心勃勃的目标，我们将使用各种技术，从测量单细胞中离子的通过（当膜正常或改变时）到氯离子通道的遗传修饰。重要的是，我们将联合收割机结合我们在细胞生物学方面的专业知识与工业界的同事，谁拥有发现和开发新药的具体技能。我们的工作将揭示细胞生物学的新方面，并从长远来看，导致新药物的产生。

We run on electricity - virtually all vital functions like the beating of the heart, the activity of our brain, the function of blood vessels or muscle contractions are triggered by tiny electrical currents that occur through the surface (membrane) of each cell. Responsible for these currents are ion channels, proteins that form microscopic gated pores that selectively allow charged ions to move in and out of the cell; the electrical impulses they generate initiate the vast array of events indispensable for life, such as those mentioned above.A class of ion channels that are found in many cell types in the body are those that allow chloride ions to move across the membrane. For example, these chloride channels are found in the muscle cells that line blood vessels. When the channel is open, chloride "currents" are activated and the blood vessel contracts; when the channel is closed, the current is suppressed and the blood vessel is relaxed. In this way, the blood can be directed to various parts of the body depending on the need. One special feature of this channel is that its opening and closing is regulated by the membrane itself. The membrane is made of oily substances (such as cholesterol) and changes in the composition of the "oils" (technically "lipids") that make up the membrane can affect the function of these chloride channels and, as a consequence, affect many aspects of body biology. The lipid composition itself is controlled by other cellular compartments such as the lysosome that is a specialised part of the cell. We have discovered that if lysosomes are not working properly, the chloride channels are also affected. We now want to understand exactly how this happens and make use of this new knowledge to design new molecules that could eventually be used to control the function of the chloride channels and address many diseases such as those involving blood vessels (e.g. high blood pressure, stroke etc.) and generally diseases in which lipid content is altered (such as a debilitating rare genetic disease known as Niemann-Pick disease type C).To achieve this ambitious aim, we will use a variety of techniques from measurement of the passage of ions in single cells (when the membrane is normal or altered) to genetic modifications of the chloride channel. Importantly, we will combine our expertise in cellular biology with that of colleagues in Industry, who have specific skills in discovering and developing new medicines. Our work will shed light on new aspects of cell biology and, in the longer term, lead to the generation of new medicines.