Clinical Research Medical

Eva Tomas, Ph.D.

*** ********* ******, *********, ** 02139 857-***-**** (mobile) **********@*****.***

April 2018 Received training throughout SOCRA (using CITI program)

Basic/refresher course Human Subject Research

oBelmont Report and its principals

oIRB regulations and Review process

oResearch involving vulnerable subjects: workers, prisoners, children, pregnant women, fetuses, neonates

oInternational and FDA- regulated research studies.

oConflicts of Interest in human research

Biomedical Responsible Conduct of Research

oResearch misconduct

oData management, Peer Review and Authorship

oMentoring

oResearch involving human subjects

oCollaborative Research

Good clinical Practice (US FDA focus)

oInformed consent in clinical trials of drugs, Biologics and devices

oOverview of new drug development

oOverview of ICH GCP including ICH GCPE6 and US FDA regulations

oInvestigator obligations in FDA-regulated research

oAudits and Inspections of clinical trials

oReporting serious adverse effects

oMonitoring of Clinical trials by Industry Sponsor

RESEARCH EXPERIENCE

Pfizer Inc. Cambridge, MA

Internal medicine and Neuroscience

2014- 2107 (August) Senior scientist, Discovery

oIdentification and validation of novel proteins and regulators in the subcellular GLUT4 compartments to identify targets for the treatment of insulin resistance and type 2 diabetes

(Subcutaneous and IP dosing route, muscle excision, blood collection and WB. Ex vivo muscle studies)

oIdentification and validation of human primary brown adipocytes as a platform to identify targets for the treatment of obesity

(Primary cell culture)

oEstablish a platform to classify therapeutic targets for anti-obesity treatments

(Seahorse XF extracellular flux analyzer)

Massachusetts General Hospital/ Harvard Medical School Boston, MA

Department of Medicine, Laboratory of Molecular Endocrinology

2012-2014 Assistant in Biology

oDetermined the role of C-terminal-derived GLP-1 peptides in energy metabolism

(DIO models, CLAMPs studies)

oDesigned and executed the in vivo experimental outlines to address the pharmacokinetics and pharmacodynamics of the C-terminal-derived GLP-1 peptides in obesity/DIO models

(Surgical pump implantation, blood collection via tail nick and cardiac puncture, tissue collection)

oEvaluated the role of C-terminal-derived GLP-1 peptides in insulin sensitivity

(Glucose and insulin tolerance tests, tail nick blood collection)

oDetermined the role of C-terminal-derived peptides in oxidative metabolism by evaluating cellular bioenergetics

(Seahorse XF extracellular flux analyzer in primary hepatocytes and C2C12 muscle cells)

oDetermined the role of C-terminal-derived peptides in oxidative metabolism by exploring the AMPK/Sirt-1/PGC1-α signaling axis

oDesigned the in vivo experimental outlines to evaluate the effects of C-terminal-derived GLP-1 peptides in NASH models (pharmacokinetics and pharmacodynamics)

(NASH model,surgical pump implantation, blood collection by tail nick and tissue collection)

2010-2014 Instructor in Medicine (Harvard Medical School)

2007-2010 Postdoctoral Fellow Mentor: Joel F. Habener, MD

oIdentified novel role of Glucagon-like-peptide -1 (GLP-1)

oDesigned and conducted metabolic in vivo mouse studies (PK/PD)

(DIO mouse model, STZ-induced diabetes, pump implantation, blood collection, tissue extraction, glucose tolerance and insulin tolerance tests)

oIntroduced novel experimental procedures, including primary hepatocyte isolation and primary muscle isolation.

oMentored and trained junior scientists (both undergraduate and medical school students)

oEngaged active collaboration with Dr. Maria Febbraio at the Department of Molecular Cardiology at the Cleveland Clinic Foundation, Ohio to establish the association of the fatty acid protein binding transporter CD36 in liver and GLP-1.

oReceived training in the Design and Conduct of Clinical Trials from Massachusetts General Hospital.

Boston University School of Medicine Boston, MA

Department of Medicine, Diabetes and Metabolism Research Unit

2000-2007 Postdoctoral Fellow Mentor: Neil Ruderman, MD/PhD

oDetermined role of globular adiponectin in the activation of AMPK

Collaboration with Drs. Tsu-Shuen Tsao and Harvey Lodish, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge (MA).

oDetermined the role of adiponectin in insulin sensitivity in adiponectin null mice.

Collaboration with Dr. Philip Scherer, Albert Einstein College of Medicine, New York.

oExamined the biological activity of oligomeric forms of adiponectin

Collaboration with Dr. Tsu-Shuen Tsao and Dr. Harvey Lodish

oStudied role of exercise in the oligomeric distribution of adiponectin

Collaboration with Dr. Tsu-Shuen Tsao and Dr. Harvey Lodish

(Ex vivo muscle analysis, PK/PD, blood collection via tail nick and cardiac puncture, glucose and insulin tolerance tests, WB, PCR. Treadmill exercised rats)

2006 Fellow at Laboratory of Dr. Grahame Hardie (Division of Molecular Physiology, University of Dundee UK)

oExamined regulation of AMPK by adiponectin

(Ex vivo muscle isolation, PK/PD, Immunoisolation and kinase activity assays)

2000 Trainee at Laboratory of Dr. Jürgen Eckel (Molecular Cardiology and Diabetes Research Institute, Düsseldorf, Germany

Examined role of Rab11 in translocation of GLUT4 in primary cardiomyocytes.(Cardiomyocyte primary isolation, immunoisolation, WB)

1999-2000 Trainee at Laboratory of Dr. Paul Pilch (Boston University School of Medicine, Boston, MA, USA)

oIdentified proteins that co-localize with GLUT4

(Muscle ex vivo analysis, muscle fractionation studies, tail vein and IP dosing, glucose collection via tail nick)

SKILLS AND TECHNIQUES

In vivo pharmacology: surgery for the implantation of subcutaneous osmopumps, oral, intravenous, subcutaneous and intraperitoneal dosing, diet-induced obese and NAFLD mice models, oral/intraperitoneal glucose tolerance testing and insulin tolerance testing, pair feeding studies, maintenance of breeding mouse colonies, blood sampling, body composition analyses (DEXA imaging and EchoMRI), metabolic studies measuring VO2, RER, physical activity, accumulative food intake (CLAMS system), exercise rat models (treadmill and swimming), blood collection via tail nick and cardiac puncture, tissue collection)

PK/PD studies (pre-clinical phase): Designed and executed the in vivo experimental outlines to address the pharmacokinetics and pharmacodynamics of the C-terminal-derived GLP-1 peptides in obesity, DIO (diet induced obesity) and NASH models.

IACUC protocol (elaboration and submission)

Proof-of- principle (PoP) and Proof- of-concept (PoC): preclinical phase.

Ex vivo pharmacology: Isolation and incubation of rat and mouse skeletal muscle for ex-vivo studies on AMPK activators and adiponectin.

Mammalian cell culture: stable cell line culture including C2C12/L6E9 skeletal muscle cells, HUVEC and A549 cells, H4IIe/ HepG2 liver cells, 3T3-L1 adipocyte cells, culture of cell hybridomes for the production of ascites in vivo. Primary cell isolation and culture of hepatocytes, skeletal muscle, inguinal fat. Human primary adipocytes adult and fetal for the identification and validation of human primary brown adipocytes as a platform to identify targets for the treatment of obesity and to establish a platform to classify therapeutic targets for anti-obesity treatments

Cell biology: NAD/NADH assays, cAMP assays, triglyceride and glycerol assays from tissue and plasma, glucose production and glucose uptake assays, lipolysis assays, cellular bioenergetics assays (Seahorse XF extracellular flux analyzer) mainly in primary brown human adipocytes, dose-response curves and time-curve effects.

Biochemistry: isolation of vesicles using immobilized antibodies for immunoprecipitation studies, western blot analysis, kinase activity studies, in vitro labeling proteins, protein fractionation by SDS-PAGE both one and two dimensions, purification of monoclonal antibodies and subcellular fractionation of rat skeletal muscle and adipocytes.

PATENTS

EP272915A2 Methods of treatment using a pentapeptide derived from the C-terminus glucagon-like-peptide-1 (glp-1)

EP2344519A2 C-terminal fragments of glucagon-like-peptide-1 (glp-1)

EDUCATION

2000 Ph.D. Biology, Universidad de Barcelona (Spain)

1994 BS Biology, Universidad de Barcelona (Spain)

PUBLICATIONS

BernardoB, Lu M, Bandyopadhyay G, Li P, Zhou Y, Huang J, Levin N, Tomas EM, Calle RA, Erion DM, Rolph TP, Brenner M, Talukdar S (2015) FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models for obesity and insulin resistance. Sci Rep 8(5): 11382

Tomas E, Stanojevic V, McManus K, Khatri A, Everill P, Bachovchin WW, Habener JF (2015) GLP-1 (32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight gain in Obese Mice. Diabetes 64(7): 2409-19

Tomas E, Pierce J, Stanojevic V, Habener JF (2011) GLP-1-Derived Nonapeptide GLP-1(28-36)amide Inhibits Weight Gain and Attenuates Diabetes and Hepatic Steatosis in Diet-Induced Obese Mice. Regul Pept Aug 8; 169(1-3):43-8. Epub2011 May4

Tomas E, Stanojevic V, Habener JF (2011). GLP-1 Derived Nonapeptide GLP-1(28-36) amide Targets to Mitochondria and Suppresses Glucose Production and Oxidative Stress in Isolated Mouse Hepatocytes. Regul Pept 167 (2-3): 177-84. Epub2011 Jan 21.

Tomas E, Pierce J, Stanojevic V, Habener JF(2010). GLP-1(9-36)amide Metabolite Inhibits Weight Gain and Attenuates Diabetes and Hepatic Steatosis in Diet-induced Obese Mice. Diabetes, Obesity and Metabolism. 13(1): 26-33.

Tomas E, Stanojevic V, Habener JF (2010). GLP-1 (9-36)amide Metabolite Suppression of glucose Production in Isolated Mouse Hepatocytes. Horm Metab Res. 42(9):657-662.

Tomas E, Habener JF (2010). Insulin-like actions of glucagon-like peptide-1: dual receptor hypothesis. Trends Endocrinol Metab 21(2): 59-67.

Kelly M, Ruderman NB, Tomas E (2006). AMP-activated protein kinase and its regulation by adiponectin and interleukin-6. Scandinavian Journal of Food 50 (S2): 85-91.

LeBrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, Tomas E (2006). Thiazolidinediones can rapidly activate AMP-activated protein kinase independent of PPAR and adiponectin. Am J Physiol Endocrinol Metab. 291(1): E175-81.

Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, and Scherer PE (2006). Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to PPAR -agonists. J Biol Chem 281(5): 2654-60.

Tomas E, Kelly M, Xiang X, Tsao TS, Keller C, Keller P, Luo Z, Lodish H, Saha AK, Unger R, Ruderman NB (2004) Metabolic and hormonal interactions between muscle and adipose tissue. Proc Nutr Soc 63(2): 381-385

Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB, Heuser JE, Lodish HF (2003) Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways. J Biol Chem 278 (50): 50810- 50817.

Tomas, E, Tsao, TS, Saha, AK, Murrey, HE, Zhang, CcC, Itani, S, Lodish, HF, Ruderman, NB. (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinas activation. Proc Natl Acad Sci USA 99(25): 163**-*****.

Tomas, E, Zorzano, A, Ruderman, NB. (2002) Exercise and insulin signaling: a historical perspective. J Appl Physiol. 93(2): 765-772.

Tomas, E, Lin, YS, Dagher, Z, Saha, A, Luo, Z, Ido, Y, Ruderman, NB. (2002) Hyperglycemia and insulin resistance: possible mechanisms. Ann N Y Acad Sci 967: 43-51 (review).

Iglesias, MA, Ye, JM, Frangioudakis G, Saha, AK, Tomas, E., Ruderman, NB, Cooney, GJ, Kraegen, EW, (2002) AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51 (10): 2886-2894.

Becker, C., Sevilla, L., Tomas, E., Palacin, M., Zorzano, A., Fisher, Y. (2001) The endosomal compartment is an insulin-sensitive recruitment site for GLUT4 and GLUT1 glucose transporters in cardiac myocytes. Endocrinology 142 (12): 5267-5276.

Tomas, E., Sevilla, L., Palacin, M., Zorzano, A., (2001) The insulin-sensitive GLUT4 storage compartment is a postendocytic and heterogeneous population recruited by acute exercise. Biochemical and Biophysical Research Communications 284: 490-495.

Kessler, A., Tomas, E., Immuler, D., meyer, HE., Zorzano, A., Eckel, J. (2000) Rab11 is Associated with GLUT4-containing Vesicles and Redistributes to Plasma Membrane in Response to Insulin. Diabetologia 43(12): 1518-27.

Tomas, E., Zorzano, A. (1999) Muscle Glut4 traffic and insulin-resistant. Frontiers in Animal Diabetes.

Zorzano, A., Sevilla, L., Tomas, E., Camps, M., Guma, A., Palacin, M. (1998) Trafficking pathway of GLUT4 glucose transporter in skeletal muscle (Review). International Journal of Molecular Medicine 2:263-271.

Sevilla, L., Tomas E., Muñoz, P., Guma, A., Fischer, Y., Thomas. J.,Ruiz-Montasell, B., Testar, X., Palacin, M., Zorzano, A. (1997) Characteritzation of Two Distinct Intracelullar GLUT4 Membrane Populations in Muscle Fiber. Differential Protein Composition and Sensitivity to Insulin. Endocrinology 138: 3006-3014.

Muñoz, P., Mora, S., Sevilla, L., Kaliman, P., Tomas, E., Guma, A., Testar, X., Palacin, M., Zorzano, A. (1996) Expression and Insulin-regulated Distribution of Caveolin in Skeletal Muscle. Journal of Biological Chemistry 271: 8133-8139.

AWARDS AND HONORS

2000 Ph. D. degree with honors: maximum cum laude per unanimity

1999-2000 Fellowship Fundacion Bosh y Gimpera, Barcelona (Spain)

1997-1999 Ministerio de Educación y Ciencia (Federal Department of

Education and Science). Spain.

1998 1st Prize of the Catalan the Society of Biological Sciences. Barcelona (Spain). "Molecular Architecture of Storage Vesicles from Glucose Transporter GLUT4: Identification of Phosphoprotein p110."

1995-1996 Instituto de Salud Pública (National Institute of Health). Spain

1993-1994 Departamento de Bioquímica y Biología Molecular

Universidad de Barcelona (Spain)

ORAL AND POSTER PRESENTATIONS

Boston Ithaca Islet Club Meeting. Boston, MA, USA March 29-30, 2014. GLP-1(32-36)amide pentapeptide regulates oxidative metabolism by activating AMPK signaling and raising the NAD+/NADH ratio in C2C12 skeletal muscle cells.

73rd Meeting &Scientific Sessions of American Diabetes Association. Chicago, USA, June 21-25, 2013.

72nd Meeting &Scientific Sessions of American Diabetes Association. Philadelphia, USA, June 8-12, 2012 (1915P)

71st Meeting &Scientific Sessions of American Diabetes Association. San Diego, USA, June 24-28, 2011. (96OR, 463P). Moderator for the guided poster session: “Pharmacological agents for obesity”.

64th Meeting &Scientific Sessions of American Diabetes Association. Orlando, USA, June 4-8, 2004. (268OR, 1529P, 1862P)

66th Annual Meeting &Scientific Sessions of American Diabetes Association. Washington DC, USA, June 9-13, 2006 (52OR, oral presentation)

FASEB Summer Research Conferences. Snowmass, Colorado, USA, August12-17, 2006.

4th Annual SMOLENICE Meeting. Bratislava, August 2001. Oral presentation: Hyperglycemia and Insulin Resistance: Possible Mechanisms.

Parc Científic de Barcelona”. Barcelona, Spain, April 26, 2004: Metabolic Effects of Adiponectin/Acrp30 in Rat Skeletal Muscle.

REFERENCES: Available on request

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