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

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.

Cerebral blood flow is increased by neuronal activity. This is necessary to ensure an adequate energy supply to reverse the ion movements generating synaptic and action potentials. Blood flow control is in large part at the level of capillaries, where pericytes contract or relax to alter capillary diameter. TPericyte malfunctions lead to pathology: during ischaemia, pericytes contract and then die in rigor, hampering restoration of blood flow to capillaries, and they are known to contract early in Alzheimer's disease. Thus, explaining pericyte contraction is key for developing new therapies for these debilitating disorders. Our newly published and unpublished data demonstrate that the TMEM16A chloride channel, which is abundantly expressed in cerebral pericytes, is a key determinant of pericyte tone. Pathophysiological activation of the channel during acute ischaemia leads to pericyte contraction and death. Here we will characterise the involvement of the channel in response to maladaptive conditions.

Our aims are to: (i) understand the cellular and whole organ consequences of gain and loss of TMEM16A function in experimental animals and cellular disease models and (ii) to examine the possibility of modulating TMEM16A function pharmacologically for therapeutic ends, in vivo.

This will be achieved by:

(i) Defining the contribution of the TMEM16A channel in mouse models of altered cerebral microcirculation.
(ii) Defining possible novel channelopathies caused by TMEM16A channel dysfunction.
(iii) Examining the effects of new TMEM16A modulators on the cerebral microcirculation in vitro and in vivo in disease models.

This study aims to reveal novel aspects of pericyte physiology and to translate this knowledge for therapeutic benefit.