Multidisciplinary Cardiovascular Research Centre
Cardiovascular discovery and therapeutics
David J Beech: Research Lab
Research interests, background and current projects
Since the final year of my undergraduate studies in 1985 my research interest has been ion channels - primarily as they relate to vascular physiology, disease and therapeutics. My lab's current interests lie in chemical regulation of newly-discovered calcium-permeable channels that play roles in tissue remodeling of vascular disease and cancer. The channels include the TRP channels and Orai channels.
General (lay) introduction to ion channels: Ion channels are proteins; tiny machines in the body that are not visible to the naked eye. There are many types, each forming a miniature doorway between compartments (cells) in bodily organs (e.g. the heart) or between sub-cellular compartments. The channels control the flow of ions (electrically charged atoms) in response to specific signals, depending on the state of health or disease. This controlled movement of ions has surprisingly crucial roles throughout the body, including in determining nerve conduction, heart rate, blood pressure, immune responses and blood sugar levels. Important classes of therapeutic drug act via ion channels, including local and general anaesthetics, anti-hypertensive agents, and drugs used to treat diabetes. Through continued research we aim to provide more understanding of these complex proteins and develop new treatments for disease.
Background on TRP channels: Knowledge of TRP channels arose from studies of the Transient Receptor Potential (TRP) of photoreception in the Drosophila melanogaster fly. Mammals are considered to have 28 TRP channels. Most are widely expressed and several show importance in human disease, including polycystic kidney disease. Mammalian TRP channels appear to exist mostly to couple relatively slow chemical and physical events to cellular calcium-signaling systems. Intriguingly, several of the activating chemicals are dietary factors: Perhaps the best known is capsaicin, which activates TRPV1 channels, but there is also menthol acting at TRPM8 and mustard oil acting at TRPA1. These TRP channels are expressed in sensory neurones, supporting the persuasive hypothesis that TRP channels are key players in sensory perception. However, channel expression is not restricted to sensory neurones and TRP channels respond to a variety of other chemicals that are naturally present throughout the body. A mysterious subgroup of TRP channels, and one that is a focus of our lab, is the TRPC channels. It is emerging that TRPC channels are relevant to normal and disease-related tissue adaptation. TRPC activity drives proliferation and migration of vascular smooth muscle cells and inflammatory responses of the endothelium. TRPCs are up-regulated in vascular remodeling, including in human hypertension, and are down-regulated by physical exercise. There is stimulation by lipid factors and oxidative stress, factors that drive atherosclerosis. TRPCs are also implicated in angiogenesis, which is important in cardiovascular remodelling and a target of new anti-cancer drugs.
Background on Orai channels: Orai1 was discovered as a defective component in T-cell calcium-entry in severe combined immune deficiency patients. Although there has been focus of research on the immune system, Orai1 is widely expressed. Reports on Orai1 in other systems are few but an important link to breast cancer cell migration and metastases has already emerged. Furthermore, there is clear expression in blood vessels, including in vascular smooth muscle cells and endothelial cells. Orai1 is predicted to be a membrane-spanning protein with some features of proteins in the well-studied tetraspanin family, which have roles in the regulation of mammalian cell morphology, motility, invasion, signaling and protein trafficking. Although tetraspanins or tetraspanin-like proteins have not been considered to be ion channels, and Orai1 lacks structural characteristics of known ion channels, recent studies suggest Orai1 is the ion pore-forming subunit of a special type of highly calcium-selective channel that is linked to intracellular calcium stores via the STIM1 protein. There is also Orai2 and Orai3.
Example projects
Integrated functions of TRPC channels in vascular smooth muscle cells
The research is focused on TRPC heteromultimeric ion channels in the context of the vascular smooth muscle cell. The channel permits calcium and sodium entry across the plasma membrane and consequently has impact on intracellular calcium homeostasis. Recent findings support the hypothesis that the channel is a complex polymodal sensor of endogenous lipid and redox factors. Goals of the research are to: develop a more complete picture of the range of endogenous activators and modulators of the channels and test the hypothesis that the channels are sensors of mechanisms regulating the lipid and redox status of the cells; reveal molecular mechanisms by which the channels are able to couple to key non-excitable cell functions including motility and proliferation; and elucidate the importance of the channels to cardiovascular disease. The research will advance fundamental understanding of these important ion channels, start to reveal the significance of the channels to one of the most importance disease in Western societies, and potentially provide the foundation for new therapeutic strategies. The research is funded by the Wellcome Trust.
TRPC1 channel mechanism in remodelling
TRPC channels are pivotal elements of a major signalling system in human cells. In recent years it has emerged that TRPC activity may be a primary driver of changes in blood vessels and the heart that contribute to cardiovascular diseases. The project is addressing a paradox, which is that TRPC1 is the most up-regulated TRPC protein in remodelling and yet it has only been observed to be a negative or inhibitory contributor to the overall TRPC channel function. We have a novel hypothesis to explain the paradox and a potential foundation for the rational design of new protective agents.The research is funded by the British Heart Foundation.
Oxidized phospholipid transduction mechanism of vascular cells
At least half of the European population dies from cardiovascular disease, often prematurely and following prolonged periods of disability. There is compelling evidence that this type of disease and several related diseases are caused, or accelerated, by unwanted inflammation, excessive oxidative stress, inactivity, and high fat load. Seminal studies over the past decade have identified special types of fat (lipid) in the disease conditions that are collectively referred to as oxidized phospholipids. There is excellent evidence that oxidized phospholipids play pivotal roles in cardiovascular disease but there is little fundamental understanding of how cells sense or respond to the lipids; or defend against them. In our new studies of vascular cells from patients with cardiovascular disease we have identified a striking initial reception mechanism for the lipids and, in this project, will investigate how the mechanism works and identify genes that encode the mechanism. Through this work we will provide new insight into an important and poorly understood area of human biology and lay the foundations for valuable therapeutic interventions with high relevance to major human diseases. The research is funded by the Medical Research Council.
Functions and therapeutic potential of vascular Orai/CRAC channels
The project is focused on addressing the importance and therapeutic potential of the Orai proteins and associated CRAC channels in vascular remodelling. It is also seeking to advance knowledge of a chemical blocker of the mechanism that has nanomolar potency, specificity and approximately 100-fold selectivity for the vascular compared with immune CRAC channel. Through this work we hope to significantly enhance knowledge of Orais in the vasculature and determine whether Orais provide an attractive foundation for developing therapeutic agents that could be used to treat problems of cancer and other important human diseases. The research is funded by the Medical Research Council.