Cardiovascular (Research Division)

Cell fate and cell fate decisions in the early vertebrate embryo, using the zebrafish as a model system.

Cardiovascular physiology and pathophysiology; endothelial dysfunction and oxidative stress; left ventricular hypertrophy; heart failure.

020 7848 4283

020 7188 0216/0213

In its broadest term, inflammation is a biological response to injury. Inflammatory cells such as monocytes and neutrophils are hugely important for warding off infectious agents, such as bacteria, fungi and viruses. However, on the other hand, they are also known to be major drivers of cardiovascular disease – often where there are zero infectious agents present. Understanding the differences between “septic” and “sterile” inflammation may lead to efficacious therapies that curb progression in cardiovascular disease but leave septic inflammation intact (so that our immune system can still fight infection).

We believe that understanding the difference between septic and sterile inflammation may rest with how leukocytes respond to and migrate towards an affected area. Two major components of the leukocyte migratory machinery are: (i) Cell adhesion molecules and (ii) the actin-based cytoskeleton. We wish to understand at the molecular level how these components are regulated and co-ordinated to promote blood-to-tissue migration.

We also have a strong interest in congenital immunodeficiencies, where genetic mutations or deletions in genes of the leukocyte cytoskeleton can severely impair the inflammatory response. Such patients suffer from chronic infections, which can be life-threatening.

020 7848 5196

Cardiac and vascular smooth muscle differentiation, redox dependent regulation of gene expression

We are interested in the molecular regulation of vascular smooth muscle cell (VSMC) phenotype and how it relates to vascular dysfunction in diseases such as atherosclerosis, diabetes, hypertension, chronic renal failure and ageing. Our studies have demonstrated that human VSMCs undergo a phenotypic transition when cultured in vitro. In culture, fully contractile human VSMCs convert into a pan-mesenchymal cell with the capacity to express multiple lineage markers of smooth muscle, osteoblasts, chondrocytes and adipocytes. In particular we are interested in the TGFb-superfamily of morphogens and how they regulate this VSMC plasticity. We hypothesize that similar phenotypic changes occur in vivo in the atherosclerotic plaque and during ageing and these modified, dysfunctional VSMCs contribute to vascular calcification and lipid accumulation and may apoptose or undergo cellular senescence. A major area of interest is in the regulation of vascular calcification, a detrimental process that occurs in the vessel media and in the atherosclerotic plaque. Our studies on vascular calcification in the context of atherosclerosis, diabetes and chronic renal failure have shown that it is a regulated process similar to bone formation. VSMCs in the normal artery wall constitutively express potent inhibitors of calcification, such as matrix Gla protein (MGP), whose absence results in spontaneous medial calcification. In atherosclerotic calcification and diabetic Monckebergs Sclerosis, expression of inhibitors is reduced and VSMCs express markers of both osteoblast (alkaline phosphatase, bone sialoprotein and osteocalcin) and chondrocyte (collagen II) differentiation. Human VSMCs in culture spontaneously convert to an osteo/chondrocytic phenotype, express the obligate bone transcription factor Cbfa1 and form calcified nodules. Calcification is initiated in nodules by release of apoptotic bodies (AB) and matrix vesicle (MV) like structures from VSMCs that act as a nidus for hydroxyapatite nucleation. In addition, circulating proteins present in serum have also been identified as potent inhibitors of calcification and our studies are aimed at determining the pathological processes that accelerate VSMC phenotypic change and subsequent calcification. We are particularly interested in the role of matrix vesicles in acting as the initial nidus for VSMC calcification. More recently, in a search for VSMC differentiation markers we identified a novel family of proteins called nesprins. These proteins are type II integral membrane proteins composed of multiple spectrin repeats with N-terminal paired calponin homology domains. They were originally identified a proteins of the inner nuclear membrane however they are also present in multiple cytoplasmic compartments including the ER, SR of the muscle sarcomere, Golgi and mitochondria. These proteins bind emerin and lamin and may play a role in a complex of diseases called laminopathies that include musclular dystrophies, cardiomyopathies, lipodystrophies and progeria syndromes. Nesprins may also function as linker proteins important for subcellular compartmentalization of organelles particularly in skeletal, smooth and cardiac muscle. Our studies are focussing on the role of these proteins in cardiovascular cell functions including the cell cycle, cell migration, cell ageing and nuclear and cytoplasmic signalling pathways.

Vascular smooth muscle cell (VSMC) phenotypic transition, from a contractile to a migratory phenotype is essential for vascular repair and is associated with dramatic changes in cytoskeletal organisation. We are interested in understanding the importance of nesprins, a family of cytoskeletal binding proteins that are highly enriched in contractile VSMCs and function at the nuclear envelope within the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex. This complex forms a specialised structure that physically connects the plasma membrane, cytoskeleton and nuclear lamina to form a single mechanically coupled system, essential for cytoskeletal organisation, differentiation and cell motility. We use molecular biological and biochemical approaches combined with state of the art cell biological and biophysical techniques to study the complex roles of this family of proteins.

We want to look at the organisation of the heart cell (cardiomyocyte) at a subcellular level; being interested mainly in cytoskeletal and signalling aspects:

• How are myofibrils and intercalated disks assembled in heart cells during development?
• How and if are myofibrils and intercalated disks affected in the diseased heart?
• What is the functional basis for the adaptations of cardiomyocytes during development and disease?

020 7848 6067

http://www.kcl.ac.uk/biohealth/research/divisions/randall/sections/signalling/ehler/ehlerelisabeth.aspx https://www.kcl.ac.uk/medicine/research/divisions/cardio/about/people/ehlere.aspx

+44 (0)20 7848 4306

Research interests involve the application of both in vivo and in vitro physiological and molecular techniques to investigate the response of the myocardium to the stresses of ischaemia, reperfusion and trophy. My current research programme addresses how the activation of both protective and detrimental signalling pathways may influence the outcome of these stresses. This includes studies on the role and function of p38-mitogen-activated protein kinase in cardioprotection/injury, the physiological mechanisms and adaptations during the development of heart failure and the application of novel techniques for measuring cardiac haemodynamics and contractility.

Areas of interest include:

•The signaling pathways involved in carbon monoxide (CO)-mediated cardiac protection.
•The role of the p38-MAP kinase isoforms in cardiac physiology
•The involvement of mTORC1 and mTORC2 in cardiac trophy during physiological and patho-physiological loading and unloading of the heart.
•Developing and characterizing new methodologies for measuring cardiac function in murine models.

020 7188 0966

Cardiac excitation-contraction coupling; fluorescence spectromicroscopy of Ca2+; changes in the passive and active (contractile) properties of the cardiac myofilaments in heart disease.

020 7188 5611

Regulation of intracellular Ca2+ in platelets and vascular cells. Mechanisms of platelet activation. TRP channels.

020 7848 5128

Diabetic nephropathy. Study of the mechanisms regulating vascular permeability and vascular integrity in the kidney glomerulus with the object of preventing end stage renal failure. The research programme of the Unit covers experimental research program on the mechanisms of glomerular injury in diabetes with particular focus on angiogenesis; the clinical research program investigates the mechanisms of cardiovascular renal disease in patient with diabetes.

Revealing the secrets of the genome provided the basis for a better understanding of cellular and molecular mechanisms. However, as neither the genomic sequence nor the transcriptional profile can be directly correlated with protein expression, the importance of measuring protein levels has become increasingly clear. The promise of proteomics is to perform large scale-studies of gene expression at the protein level, leading to the discovery of novel proteins, novel markers of diseases, novel pathophysiological mechanisms and, last but not least, novel targets for drug development, providing a strong impetus for investment in these new technologies. Without doubts, proteomics will redefine biomedical research in the postgenomic era. In cardiovascular research, however, proteomics is still in its infancy. Our objective is to identify protein changes in vascular disease and to translate them into a functional context by combining proteomics with other -omic technologies such as transcriptomics and metabolomics.

020 7848 5132

The group studies regulatory proteins such as MS1, myosin binding protein C, light chain kinase and the myosin light chain itself which are involved in the development of pathological hypertrophy of cardiac muscle leading to cardiomyopathy and ultimately cardiac arrest. We investigate these processes from the angle of structural and functional biology. We determine the structures of key proteins and study them in the test tube and in the cell to understand how they interact with each other and how disease causing mutations influence their function. The ultimate aim of our work is to improve the means to tackle heart disease based on a detailed understanding of their molecular base.

020 7848 6434

We are interested in the assembly and turnover of the contractile structures in cardiomyocytes, the sarcomeres, especially:

• how giant ruler proteins called titin and obscurin control the assembly of many other structural, contractile and signalling proteins into ordered sarcomeres,
• how mechanical forces regulate sarcomere assembly, as well as controlled turnover by the autophagy and ubiquitin-proteasomal pathways,
• how mutations in sarcomeric proteins, especially in titin and obscurin, affect sarcomere and turnover functions.

We use biochemical, biophysical, advanced cell imaging and structural methods to elucidate these basic functions and to translate them to human disease.

020 7848 6709

http://www.kcl.ac.uk/biohealth/research/divisions/randall/sections/signalling/gautel/gautelmathias.aspx https://www.kcl.ac.uk/medicine/research/divisions/cardio/about/people/gautelm.aspx

We are interested in exploring the molecular mechanisms underlying cardiac injury and dysfunction in ischaemia and failure and in the discovery and evaluation of novel therapies towards their amelioration. Our investigations focus on the post-translational regulation of protein function, particularly through phosphorylation/dephosphorylation reactions that are catalysed by protein kinases and phosphatases, and physiological consequences by impacting on myocardial viability, remodelling and contractile function.

Our research is focused on sudden cardiac death. We have developed several animal models for studying ventricular arrhythmias, the effects of drugs, and the effects of transgenic target modification. Our aim is simple: to identify the best ways of targeting the pathology and its associated electrophysiological dysfunction that causes cardiac arrhythmias during ischaemic heart disease - still the single largest cause of death in the UK population. We are strong proponents of bioassay, generation of clinically-relevant animal models, and pharmacological interrogation of drug action (concentration-response analysis). We work as a small team, engaging with other teams to pursue specific goals. We are keen to collaborate with the pharmaceutical industry in translational drug discovery research, and also have an interest in safety pharmacology, particularly the development of models for detecting drug-induced torsades de pointes (proarrhythmia).

020 7188 1095

020 7188 1008

Regulation and function of ion translocating proteins in cardiac muscle in health and disease. Current research focuses on the regulation of the cardiac Na/K ATPase by its accessory protein phospholemman.

Endothelial cell dysfunction in dyslipidaemia and diabetes; measurements of forearm and coronary blood flow in vivo.

The redox-dependent regulation of protein function in the setting of ischaemia and reperfusion.

The Vascular Biology Section is a basic science research unit. It undertakes a wide range of research in the field of cardiovascular diseases with the broad objective of improving the understanding of molecular mechanisms in the pathogenesis and the treatment of cardiovascular disease. The overarching aim of our study is to elucidate the molecular mechanisms underlying cardiovascular diseases, especially atherosclerosis. Our task is to bridge the gap between basic science research and its application through cardiology and cardiac surgery. In keeping with this, several research projects are carried out in the Unit as follows:
1) Stem/progenitor cells in atherosclerosis
2) Proteomics
3) Mechanical stress-initiated signalling.

020 7848 5295

Myocardial adaption; signal transduction; assessment of cellular injury. Studying the mechanisms of adaptation, cardioprotection and cell death in cardiac myocytes and fibroblasts during ischaemia-reperfusion injury, post-infarction remodelling and heart failure.

We are interested in cardiovascular nutrigenomics in diverse models of vascular disease. In particular our research is focused on how dietary plant derived nutrients interact with cellular signalling pathways to regulate expression of antioxidant defence genes to maintain vascular function during cardiovascular diseases related to ageing such as atherosclerosis, hypertension and stroke. We are also investigating how biomechanical forces such as fluid shear stress and stretch maintain the normal function of blood vessels.

Coronary physiology; coronary intervention; acute coronary syndromes.

Cardiovascular regulation, especially that relating to hypertension and peripheral blood flow. Specific emphasis on the pharmacological regulation of peptide and transient receptor potential (TRP) channel activity.

+44 (0) 20 7848 4453

Stem cells; atherosclerosis; vascular biology; animal models.