MICA: The molecular mechanisms of control of cerebral blood flow by the TMEM16A Cl- channel and their potential for pharmacological intervention

我们在日常生活中所做的一切都需要激活大脑的特定部分。当大脑区域活跃时，该区域的神经细胞（大脑中的主要信息处理细胞）需要能量。因此，血液必须转移到活动区域，以确保神经细胞获得足够的氧气和营养来为其工作提供动力。这个过程依赖于包围毛细血管的周细胞。周细胞可以收缩和舒张，这样就可以将血流引导到最需要的部位。当周细胞功能失常时，就可能发生疾病。例如，在阿尔茨海默病和中风等疾病中，周细胞会过度收缩毛细血管，这会导致大脑中神经细胞的损伤。虽然我们还不完全了解周细胞是如何收缩和放松的，但我们最近的工作表明，细胞的一种成分，一种在细胞膜上形成孔（或通道）的蛋白质，称为TMEM 16 A，起着非常重要的作用。TMEM 16 A通道允许带电荷的氯离子穿过细胞膜，由此产生的电压变化触发周细胞的收缩。当通道打开时，氯离子流出细胞，周细胞收缩;当通道关闭时，这种电流被抑制，周细胞放松。在完成了这个令人兴奋的初步观察之后，我们现在希望确切地了解氯电流是如何控制周细胞的，以及这个通道的故障如何导致活脑中的问题（正如我们进行的遗传分析所建议的那样）。我们还希望知道，当周细胞收缩过多时，是否可以使用药物来阻断通道（就像瓶子中的软木塞），以防止电流并在病理条件下扩张毛细血管，例如中风和痴呆症。我们将使用各种技术，从测量周细胞中的氯电流到活体大脑中的先进显微镜，来实现这一重要目标。至关重要的是，我们将把我们在细胞和全身生物学方面的专业知识与工业界的同事结合起来，他们是发现和开发新药的专家，以及在医院工作并对大脑血管疾病有深入了解的医生。我们的工作将揭示细胞和大脑生物学的新方面，并为一系列神经系统疾病的新疗法奠定基础。

Everything we do in our daily life requires activation of specific parts of the brain. When a brain region is active, the nerve cells (the main information processing cells in the brain) in that region need energy. Consequently, blood must be diverted to the active area to ensure the nerve cells receive enough oxygen and nutrients to power their work. This process relies on cells called pericytes that surround the capillaries. Pericytes can contract and relax and, in so doing, direct blood flow to regions that most need it. Disease may arise when pericytes malfunction. For example, pericytes constrict capillaries too much in conditions such as Alzheimer's disease and stroke, and this leads to damage of the nerve cells in the brain. While we do not fully understand how pericytes contract and relax, our recent work suggests that a component of the cell, a protein that forms a hole (or channel) across the cell membrane, called TMEM16A, plays a very important role. The TMEM16A channel allows charged chloride ions to move across the cell membrane and the resulting voltage change triggers the contraction of the pericyte. When the channel is open, chloride ions flow out of the cell and the pericyte contracts; when the channel is closed, this current is suppressed and the pericyte is relaxed. Having made this initial exciting observation, we now wish to understand exactly how the chloride current controls the pericyte and how malfunction of this channel can lead to problems in the living brain (as is suggested by a genetic analysis we have carried out). We also wish to know if drugs can be used to block the channel (like a cork in a bottle) to prevent the current and dilate the capillaries in pathological conditions, such as stroke and dementia, when the pericytes contract too much. We will use a variety of techniques, from measurement of chloride currents in pericytes to advanced microscopy in the living brain, to address this important aim. Crucially, we will combine our expertise in cellular and whole body biology with that of colleagues in industry, who are experts in discovering and developing new medicines, and doctors who work in hospitals and have intimate understanding of diseases of blood vessels of the brain. Our work will reveal new aspects of cell and brain biology and lay the foundation for new treatments for a range of neurological conditions.