Collaborations between the Evans Center and Warwick Medical School (UK)

Warwick Medical School ARC Affiliates: Research profiles of PIs within the Division of Metabolic & Vascular Health, Warwick Medical School (UK), who are affiliated with Evans Center ARCs

Led by Dr. Victor Zammit (Division of Metabolic & Vascular Health, Warwick University) and Dr. Katya Ravid (Evans Center Director)

Dr. Harpal  Randeva (Associate Clinical Professor)

http://www2.warwick.ac.uk/fac/med/staff/randeva

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

Dr. Randeva is a clinician scientist and his research interests span both basic science and clinical science/translational, with research programs in the area pertinent to energy balance, obesity, cardiovascular, endocrinology and women’s health.  The work which is currently ongoing is as follows:

Adipose Tissue Biology – our focus is on the regulation of adipogenesis in both WAT and BAT in both humans and rodents. In addition, the role GPCRs in adipose tissue biology is being studied, e.g. Orexin, Chemerin. Neuro-peptide and adipokine mediated modifications of molecular signatures in BAT and more importantly factors governing “britening” of WAT.

Vascular & Cardiac Biology – the role of GPCR ligands (e.g chemerin) and adipokines on endothelial angiogenesis and their effects in influencing vascular reactivity in health and disease using wire-myograph system. Cardiovascular pharmacology-studying the effects of adipokines and hepatokines on cardiac function/ infarct risk, using the Langendorff system, working heart model and in-vivo.

Molecular Endocrinology – investigating the specific G-proteins that are linked to orexin and chemerin receptors, and elucidating the intracellular signal transduction pathways of these receptors in both human and rodent tissues. Cloning and characterising the promoter regions of these receptors is another area of interest. Additionally, investigating G-protein coupled receptor dimerization using co-immunoprecipitation, various adaptations of fluorescent resonance energy transfer (FRET and BRET) techniques. Polycystic Ovary Syndrome (PCOS) – PCOS is a multi-faceted metabolic disease linked with insulin resistance, obesity, dyslipidaemia, increased incidence of Type II diabetes and elevated blood pressure.  These women are at increased risk of cardio-vascular disease.  Our translational research focuses on identifying novel molecules involved in the insulin resistance state of these women, but more importantly how these molecules can play a role in the phenotype of this condition.  Additionally, we have investigated the impact of exercise/lifestyle modification, including diet and pharmacological intervention in the form of Metformin therapy.

Women’s Health/Pregnancy – In brief, this comprises of a wide area of clinical research involving women with sub fertility and infertility, women with Turner’s Syndrome, post-menopausal women with cardio-metabolic features. For example, we have shown that the route of administration of HRT has an important part to play in determining and increasing levels of certain cardiovascular risk factors, such as MMPs.  We are investigating (with Mr Vatish) the impact of obesity during pregnancy on cardiometabolic signatures in both mother and offspring, and also in site specific adipose tissue from mothers.

1) Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes 2011;60:2758-62.

2) Ramanjaneya M, Chen J, Brown JE, Tripathi G, Hallschmid M, Patel S, Kern W, Hillhouse EW, Lehnert H, Tan BK, Randeva HS. Identification of nesfatin-1 in human and murine adipose tissue: a novel depot-specific adipokine with increased levels in obesity. Endocrinology 2010;151:3169-80.

3) Adya R, Tan BK, Punn A, Chen J, Randeva HS. Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc Res 2001;356-65.

4) Chen J, Randeva HS. Genomic organization and regulation of the human orexin (hypocretin) receptor 2 gene: identification of alternative promoters. Biochem J 2010;427:377-90.

5) Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Cardiometabolic Aspects of the Polycystic Ovary Syndrome. Endocrine Reviews 2012; Jul 24. [Epub ahead of print]

 

Dr. Claire Bastie (Assistant Professor)

http://search.warwick.ac.uk/profile?id=MTA3MzgxMGYxODJlYmU%3D

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

The Bastie laboratory is focused on dissecting the molecular basis of obesity and diabetes utilizing both whole animal physiology with genetically modified animal models (conventional knockouts, tissue-specific knockouts and over-expressing models) and explant cultures coupled with advanced molecular and cellular biology tools. The main interests of our laboratory are concentrated on:

1) characterizing Fyn kinase, a non-receptor tyrosine kinase, as a novel element of the nutrient-sensor system that regulates whole body energy homeostasis in conditions of either excess (obesity) or deprivation (caloric restriction) of nutrient availability and

2) characterizing Fyn kinase as a core enzyme co-ordinating a number of key processes associated with aging.

Recently, we identified that Fyn deficient animals are lean and display enhanced insulin sensitivity, glucose tolerance, low fasting glucose levels and improved lipid profiles (1). Additionally, pharmacological inhibition of Fyn kinase recapitulates some of the metabolic effects observed in the Fyn deficient mice and results in loss of fat mass (2). We are currently a) examining the upstream and downstream pathways regulating Fyn function, focusing on the cross-talk between Fyn kinase and AMPK in adipose tissue and muscle; b) determining the metabolic events leading to this weight loss, using peripheral and central injections of Fyn inhibitors in different animals models, specifically looking at the control of food intake; c) dissecting the hepatic control of glucose production after a long fast and how Fyn kinase regulates this process.

Another aspect of our research aims at determining the role of Fyn kinase in diet-induced obesity, particularly focusing on the molecular mechanisms involved in adipose tissue inflammatory processes.

The latest project of the Bastie Laboratory focuses on identifying new targets that are regulated by Fyn kinase using RNA high sequencing in muscle, that are involved in autophagy and sarcopenia.

 

1) Yamada, E., Bastie, CC., Koga, H., Yang, Y., Cuervo, AM and Pessin, JE. Mouse skeletal muscle fiber-type specific macroautophagy and muscle wasting is regulated by a Fyn/STAT3/Vps34 signaling pathway. Cell Rep. 2012 May 31;1(5):557-569.

2) Yamada, E., Pessin,JE., Kurland, IJ., Schwartz, GJ., and Bastie, CC.Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation and nuclear export of LKB1. Cell Metab. 2010 Feb 3;11(2):113-24.

3) Bastie, CC., Zong, H.H., Xu, J., Busa, B., Judex, S., Kurland, I.J, and Pessin, JE. Integrative Metabolic Regulation of Peripheral Tissue Fatty Acid Oxidation through Signaling Crosstalk Between Insulin and the Src Kinase Family Member Fyn. Cell Metab. 2007 May;5(5):371-81

4) Yamada, E., Lee, TWA., Pessin, JE and Bastie, CC. Targeted therapies of the LKB1/AMPK pathway for the treatment of insulin resistance. Future Medicinal Chemistry (UK). 2010, Vol2, Number 12

 

 

Dr. Philip G McTernan (Associate Professor)

http://www2.warwick.ac.uk/fac/med/staff/mcternan/

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

Obesity represents the single most important contributor to type 2 diabetes mellitus (T2DM) and cardiovascular disease risk, with adipose tissue (AT) currently perceived as an important site of overlapping metabolic and immune function. Within this, AT is also recognised as an endocrine organ, with the ability to have adverse effects on other organs due, in part, to adipocytokines, which directly influence the brain, liver, heart and skeletal muscle. Furthermore, the recognition that AT may have an inflammatory role, as adipocytes contain components of the innate immune pathway, offers further possibilities for relating obesity with chronic sub-clinical inflammation. In addition to this it is clear that the functionality of adipose tissue, affected by fat distribution, age, gender, ethnicity, menopausal status, disease state, feeding, alters many metabolic pathways. As such examining human AT can give us a better understanding as to the influence of AT on human metabolism. Our main focus has been to work with human samples examining the pathophysiological changes in adipocyte function in metabolic diseases. The team consists of basic science and clinical postgraduate students, postdocs and clinicians working on several key areas of research in this area

•            Sub-clinical inflammation in pre-T2DM

•            Postprandial Metabolism and its influence on inflammatory response

•            Mitochondrial dysfunction in AT

•            Appetite Control & its dysregulation in obesity

•            Ageing and Insulin resistance

•            New and Known ‘Adipocytokines’: peripheral and central action

Human Blood Analysis: Work has centred on using collected human serum, plasma or CSF from a variety of human studies: obesity and diabetes studies: NAFLD studies, Gestational diabetes studies, menopausal studies, high fat meal studies, high glucose meal studies, meal frequency studies, bariatric Surgery studies pre and post weight loss, HIV studies, and CVD studies.

Human Tissue: A bank of tissues and cells has been accumulated as a result of numerous human AT studies on AT (Abdominal Sc, Omental AT, Thigh Sc, epicardial AT, human skeletal, myocardial tissue), cultured pre-adipocytes, mature adipocytes, and cell lines (human and mouse).

Techniques: human in vitro primary and secondary adipocyte cell cultures, differentiation studies, RT-PCR, microarray, Western Blots, Bioplex, ELISA, Endotoxin (LPS) assay, Seahorse analysis, lipolysis, lipogenesis studies, confocal microscopy, whole body calorimeter unit as part of human studies, energy expenditure studies as well as needle biopsy human AT culture studies.

1) Harte AL, Varma MC, Tripathi G, McGee KC, Al-Daghri NM, Al-Attas OS, Sabico S, O’Hare JP, Ceriello A, Saravanan P, Kumar S, McTernan PG. High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care. 2012 Feb;35(2):375-82.

2) Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NFκB and JNK in human abdominal subcutaneous adipocytes. McGee KC, Harte AL, da Silva NF, Al-Daghri N, Creely SJ, Kusminski CM, Tripathi G, Levick PL, Khanolkar M, Evans M, Chittari MV, Patel V, Kumar S, McTernan PG. PLoS One. 2011;6(6):e20287. Epub 2011 Jun 9.

3) Baker AR, Harte AL, Howell N, Pritlove DC, Ranasinghe AM, da Silva NF, Youssef EM, Khunti K, Davies MJ, Bonser RS, Kumar S, Pagano D, McTernan PG. Epicardial adipose tissue as a source of nuclear factor-kappaB and c-Jun N-terminal kinase mediated inflammation in patients with coronary artery disease. J Clin Endocrinol Metab. 2009 Jan;94(1):261-7. Epub 2008 Nov 4

4) Kusminski CM, McTernan PG, Schraw T, Kos K, O’Hare JP, Ahima R, Kumar S, Scherer PE. Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum. Diabetologia. 2007 Mar;50(3):634-42

 

Dr. Gyanendra Tripathi (Associate Professor)

http://www2.warwick.ac.uk/fac/med/staff/tripathi/

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

The current focus of my research is to understand the pathogenesis of obesity linked type 2 diabetes mellitus (T2D).  The research in my lab is mainly focussed on:

Inflammation and Endoplasmic Reticulum (ER) Stress:   We have discovered that salicylates and other chemical chaperones can alleviate the ER stress and insulin resistance induced by lipopolysaccharides and high glucose in primary human adipocytes. We are currently dissecting the individual ER stress pathways involved in inducing inflammation in adipocytes.

Mitochondrial Metabolism:  We have recently discovered that obesity causes dysregulation of mitochondrial dynamics in human adipose tissue. Both mitochondrial fusion and fission are affected along with oxidation.

Adipokine signalling and Adipogenesis: We are studying the downstream signalling pathways of these adipokines using 3T3-L1 and human primary adipocytes. We are also interested in discovering novel pathways and inducers of adipogenesis in primary human adipocytes.

Role of micronutrients Vitamin B12 and Folate in epigenetic programming: Our studies are aimed at providing important information on the role of these micronutrients in the processes of adipogenesis and lipolysis.

Novel genes of inflammation: Using a systems approach we have identifie novel targets of inflammation in human adipose tissue. We have identified a novel gene with anti-inflammatory propertie in primary human adipocytes and also in the human adipocyte cell line Chub S-7.

Role of IGF signalling in primary human adipocytes:    Our studies provided solid evidence for IGF-independent in vivo role for IGFBP-5 in growth and development. Iin human adipose tissue.

1) Schisano B, Harte AL, Lois K, Saravanan P, Al-Daghri N, Al-Attas O, Knudsen LB, McTernan PG, Ceriello A, Tripathi G. (2012) GLP-1 analogue, Liraglutide protects human umbilical vein endothelial cells against high glucose induced endoplasmic reticulum stress. Regul Pept. 174(1-3):46-52.

2) B. Schisano, G. Tripathi, K. McGee, P. G. McTernan and A. Ceriello (2011) Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells.Diabetologia 54(5):1219-26. Joint First Author

3) Harte AL, Varma MC, Tripathi G, McGee KM, Al-Daghri NM, Al-Attas OS, Sabico S, O’Hare JP, Ceriello A, Saravanan P, Kumar S, McTernan PG (2012) High Fat Intake leads to Acute Post-Prandial Exposure to Circulating Endotoxin in Type 2 diabetes mellitus Subjects. Diabetes Care35(2):375-82.

4) S. Alhusaini, K. McGee, B. Schisano, A. Harte, P. McTernan, S. Kumar and G. Tripathi (2010) Lipopolysaccharide, High Glucose and Saturated Fatty Acids induce endoplasmic reticulum stress in cultured primary human adipocytes: Salicylate alleviates this stress. Biochem Biophys Res Comm.397(3):472-478

5) M. Ramanjaneya, J. Chen, J. Brown, G. Tripathi, M. Hallschmid, S. Patel , W. Kern, E. W. Hillhouse, H. Lehnert, B. K. Tan and H. S. Randeva (2010) Identification of nesfatin-1 in human and murine adipose tissue: A novel depot-specific adipokine with increased levels in obesity. Endocrinology. 151(7):3169-3180.

 

 

Dr. Naila Rabbani (Associate Professor)

http://www2.warwick.ac.uk/fac/med/staff/rabbani/

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Obesity, Cancer and Inflammation (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/obesity-cancer-and-inflammation/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

RESEARCH INTERESTS:

Proteomics of protein damage

■       Quantitation of protein damage makers and mapping to susceptible proteins and sites within them – particularly by dicarbonyl glycation (dicarbonyl proteome) in disease mechanism.

■       Development of gold standard analytical techniques for clinical biochemistry

Lipoprotein metabolism

■     Effects of dicarbonyl glycation on LDL atherogenicity, metabolism and residence time.

■     Study of HDL subfraction in patients with high risk of vascular complications – quality vs. quantity of HDL which matters the most?

■     Characterisation of the role of vascular dicarbonyl stress in the development of atherosclerosis in CVD and the development of a mouse model.

Biomarker discovery in Arthritis and Obesity

■     Identification and validation of novel diagnostic biomarker for early detection of rheumatoid and osteoarthritis.

■     Identification and validation of novel biomarker in obesity for predicting progression to diabetes and CVD.

Dysfunctional metabolism of thiamine in diabetes and the development of vascular complications of diabetes

■      Dysfunctional metabolism of thiamine in experimental and clinical diabetes.

■      Thiamine supplements for prevention and reversal of early-stage diabetic complications.

1) Rabbani, N., Godfrey, L., Xue, M., Shaheen, F., Geoffrion, M., Milne, R. and Thornalley, P.J. (2011) Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity. A Possible Contributor to Increased Risk of Cardiovascular Disease in Diabetes. Diabetes 60, 1973-1980

2) Thornalley, P.J., Waris, S., Fleming, T., Santarius, T., Larkin, S.J., Winklhofer-Roob, B.M., Stratton, M.R. and Rabbani, N. (2010) Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids Research 38, 5432-5442.

3) Rabbani, N. and Thornalley, P.J. (2011) Emerging role of thiamine therapy for prevention and treatment of early stage diabetic nephropathy. Diabetes, Obesity and Metabolism 13, 577 – 583

4) Xue, M., Rabbani, N., Momiji, H., Imbasi, P., Anwar, M.M., Kitteringham, N., Parks, B.K., Souma, T., Moriguchi, T., Yamamoto, M. and Thornalley, P.J. (2012) Transcriptional control of glyoxalase 1 by Nrf2 provides a stress responsive defence against dicarbonyl glycation. Biochem. J. 443, 213 – 222.

5) Bierhaus, A., Stoyanov, S., Fleming, T., Sauer, S.K., Leffler, A., Babes, A., Kichko, T.I., Neacsu, C., Konrade, I., Pirags, V., Lukic, I.K., Morcos, M., Dehmer, T., Rabbani, N., Thornalley, P.J., Edelstein, D., Nau, C., Forbes, J., Stern, D.M., Cooper, M.E, Humpert, P.M., Brownlee, M., Reeh, P. and Nawroth, P.P. (2012) Metabolic hyperalgesia – a novel concept based on the reactive metabolite methylglyoxal and the sensory neuronal Na+ channel Nav1.8. Nature Medicine 18, Pages:926–933

Dr. Paul J Thornalley (Professor of Systems Biology & Protein Damage)

http://www2.warwick.ac.uk/fac/med/staff/thornalley/

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

RESEARCH INTERESTS:

Proteomics of protein damage

■          Quantitation of protein damage and mapping to susceptible proteins and sites within them    – particularly by dicarbonyl glycation (dicarbonyl proteome) in diabetes.

■           Prevention of dicarbonyl glycation damage by the glyoxalase system.

■           Therapeutics development of glyoxalase 1 (Glo1) inducers and Glo1 inhibitors

Antistress gene response in diabetes, renal failure and ageing

■           Transcriptional control of protective gene expression by transcription factor Nrf2.

■          Activation of the anti-stress gene response for good vascular and metabolic health, prevention and reversal of vascular complications of diabetes and healthy ageing.

Dysfunctional metabolism of thiamine in diabetes and the development of vascular complications of diabetes

■        Dysfunctional metabolism of thiamine in experimental and clinical diabetes.

■        Thiamine supplements for prevention and reversal of early-stage diabetic complications.

1) Santarius, T., Bignell, G., Greenman, C.D., Widaa, S., Chen, L., Mahoney, C.L. Butler, A., Edkins, S., Waris, S., Thornalley, P.J., Futreal, A. and Stratton, M.R. (2010) GLO1- a novel amplified gene in human cancer. Chromosome, Genes and Cancer 49, 711-725

2) Thornalley, P.J., Waris, S., Fleming, T., Santarius, T., Larkin, S.J., Winklhofer-Roob, B.M., Stratton, M.R. and Rabbani, N. (2010) Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids Research 38, 5432-5442.

3) Murphy, M.P., Holmgren, Nils-Göran Larsson, A., Halliwell, B., Chang, C.J., Kalyanaraman, B., Rhee, S.G., Thornalley, P.J., Partridge, L., Gems, D., Nyström, T., Belousov, V., Schumacker, P.T. and Winterbourn, C.C. (2011) Unravelling the Biological Roles of Reactive Oxygen Species. Cell Metabolism 13, 361-366.

4) Rabbani, N. and Thornalley, P.J. (2011) Emerging role of thiamine therapy for prevention and treatment of early stage diabetic nephropathy. Diabetes, Obesity and Metabolism 13, 577 – 583

 

5) Rabbani, N., Godfrey, L., Xue, M., Shaheen, F., Geoffrion, M., Milne, R. and Thornalley, P.J. (2011) Glycation of LDL by methylglyoxal increases arterial atherogenicity. a possible contributor to increased risk of cardiovascular disease in diabetes. Diabetes 60, 1973-1980

6) Xue, M., Rabbani, N., Momiji, H., Imbasi, P., Anwar, M.M., Kitteringham, N., Parks, B.K., Souma, T., Moriguchi, T., Yamamoto, M. and Thornalley, P.J. (2012) Transcriptional control of glyoxalase 1 by Nrf2 provides a stress responsive defence against dicarbonyl glycation. Biochem. J. 443, 213 – 222.

7) Bierhaus, A., Stoyanov, S., Fleming, T., Sauer, S.K., Leffler, A., Babes, A., Kichko, T.I., Neacsu, C., Konrade, I., Pirags, V., Lukic, I.K., Morcos, M., Dehmer, T., Rabbani, N., Thornalley, P.J., Edelstein, D., Nau, C., Forbes, J., Stern, D.M., Cooper, M.E, Humpert, P.M., Brownlee, M., Reeh, P. and Nawroth, P.P. (2012) Metabolic hyperalgesia – a novel concept based on the reactive metabolite methylglyoxal and the sensory neuronal Na+ channel Nav1.8. Nature Medicine 18, Pages:926–933

Dr. Daniel Zehnfer(Associate Clinical Professor)

http://www2.warwick.ac.uk/fac/med/staff/zehnder/

Evans Center ARC Affiliate: Molecular, Biomechanical and Genetic Mechanisms of Arterial Stiffness (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mechanisms-and-treatment-of-arterial-stiffness/)

 

Dr. Zehnder is clinical investigator in the field of endocrine nephrology with focus on the vitamin D hormonal system, calcium sensing receptor and on chronic disease mediated accelerated cardiovascular disease. The clinical environment at the University Hospital Coventry and Warwickshire (UHCW) with a catchment population of more than one million and the research environment at one of the UKs leading Universities, His laboratory focuses on translational human research and we have particular expertise in arterial, vascular smooth muscle cell, endothelial cell biology, cross-sectional and interventional clinical studies. He has built a bank of  over 300 human arteries, serum samples, clinical date, including clinical characterization of arterial elasticity to-date. This will allow him to perform a comprehensive investigation of molecular risk markers and target molecules with the aim to find mechanisms to modulate diffuse arterial disease.

Recent research has included a study on  the role of Klotho in premature vascular aging, a major contributor to cardiovascular disease in patients with chronic kidney disease, conducted in collaboration with Dr. Li-Li Hsiao at Harvard Medical School, Brigham and Women’s Hospital in Boston, MA, USA. They have been collaborating on multiple projects since 2008 and theirmost recent publication together in Circulation provides evidence of the maturity and success of this collaboration. They have also obtained funding from Abbott Laboratories for our functional human vascular genomics project.

1) Lim, K., Lu, T.S., Molostvov, G., Zehnder, D., Hsiao, L-L. (2012) “Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to FGF-23”. Circulation, 125(18), 2243-55. *Co-senior author.

2) Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson BT, Andress D, Zhang W, Packham D, Singh B, Zehnder D, Shah A, Pachika A, Manning WJ, Solomon SD. (2012). “Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial.JAMA. Feb 15;307(7):674-84.

3) Thadhani R, Appelbaum E, Chang Y, Pritchett Y, Bhan I, Agarwal R, Zoccali C, Wanner C, Lloyd-Jones D, Cannata J, Thompson T, Audhya P, Andress D, Zhang W, Ye J, Packham D, Singh B, Zehnder D, Manning WJ, Pachika A, Solomon SD. (2011). “Vitamin d receptor activation and left ventricular hypertrophy in advanced kidney disease.Am J Nephrol.;33(2):139-49

4)  Ilyas R, Wallis R, Soilleux E, Townsend P, Zehnder D, Tan B, Sim R, Lehnert H, Randeva H, Mitchell D (2011). “Hyperglycaemic conditions disrupt immunological protein oligosaccharide interactions via reversible noncovalent competitive inhibition by free glucose”. Immunobiology. Jan-Feb;216(1-2):126-3

5) Rabbani N, Chittari MV, Bodmer CW, Zehnder D, Ceriello A, Thornalley PJ.(2010). “Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin. Diabetes.” Apr;59(4):1038-45.

6) Molostvov G, Fletcher S, Bland R, Zehnder D (2008). “Extracellular calcium-sensing receptor mediated signalling is involved in human vascular smooth muscle cells.” Cell Physiol Biochem.;22:413-22.

 

 

Dr. Victor Zammit (Professor of Metabolic Biochemistry)

http://www2.warwick.ac.uk/fac/med/staff/zammit/

Evans Center ARC Affiliate: Metabolic Disease and Adipose Tissue: Studies in Patients Undergoing Bariatric Surgery (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/1230-2/)

Evans Center ARC Affiliate: Mitochondria ARC (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/mtarc/)

Evans Center ARC Affiliate: Sex Differences in Adipose Tissue Regeneration (http://www.bumc.bu.edu/evanscenteribr/the-arcs/the-arcs/sex-differences/)

The Zammit laboratory studies  mechanisms involved in regulation of the pathways of fatty acid oxidation and triglyceride synthesis, primarily in the liver, as they relate to the etiology of insulin resistance.  The structure-function relationships of the mitochondrial outer membrane enzyme carnitine palmitoyltransferase 1 have been a long-standing interest of the group.  The molecular mechanisms involved in the sensing of the membrane environment by the enzyme to regulate its sensitivity to malonyl-CoA inhibition have been elucidated.  Current work is focused on the role of transmembrane domains in the oligomerisation of the protein and the interaction between the regulatory N-terminal domain and the large catalytic domain of the protein.

The elucidation of the pathway of triglyceride synthesis and secretion in hepatocytes, and the respective roles of the two diacylglycerol acyltransferases (DGAT1 and DGAT2) have been more recent interests.  It has been shown that DGAT2 and DGAT1 act in series, and that DGAT2 acts upstream of DGAT1.  DGAT2 is rate-limiting for the incorporation of new glyceride into triglycerides and de novo synthesized fatty acids into triglycerides, while DGAT1 acts to rescue partial glycerides generated by lipolysis by esterifying them with preformed fatty acids.  This work is being extended through studies into the roles of the two DGATs in the etiology of insulin resistance in cardiac and skeletal muscle.

1) Wurie, H.R, Buckett, L and V A Zammit (2012)  DGAT2 acts upstream of DGAT1 and utilizes nascent diacylgycerol and de nvo synthesised fatty acids as substrates FEBS J 279, 3033-21

2) Wurie, H.R, Buckett, L and V A Zammit (2011) Evidence that diacylglyceril acyltransferase 1 (DGAT 1) hasw dual membrane topology in the endoplasmic reticulum of HepG2 cells.  J Biol Chem 286, 36238 – 47.

3) Jennei, Z.A., Warren, G.Z., Hassan, M, Zammit V A and AM Dixon (2011)  Packing of the transmembrane domain 2 of carnitine palmitoyltransferase-1A affects oligomerization and malonyl-CoA sensitivity pf the mitochondrial membrane protein.  FASEB J 25, 4522-29.

4) Rao, J n, Warren, G Z, Estolt-Povedano, S, Zammit V A and A M Dixon (2011) An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase-1A.  J Biol Chem 286, 42545 – 54.

5) Moran, C. N., Barwell, N. D., Malkova, D., Cleland, S. J., McPhee, I., Packard, C. J., Zammit, V. A., and Gill, J. M. (2011) Effects of diabetes family history and exercise training on the expression of adiponectin and leptin and their receptors Metabolism 60, 206-214

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March 28, 2014
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