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CURRICULUM VITAE Name: DEBORAH JULIE PHIPPARD Nationality: British with permanent US resident status Education: Ph.D. University of London (1991-1994) Molecular & Cell Biology, Developmental Biology & Genetics Thesis title: Homeobox gene expression during mouse mammary gland development BSc. (Hons). South Bank University, London (1983-1987) Biotechnology & Industrial Biology Research Experience: 2009- Present Executive Director, Biomarker & Discovery Research, Immune Tolerance Network. Responsible for running a department comprised of 35 scientists, biostatisticians, programmers/data managers and operations experts, with myriad external contracts dedicated to leading mechanistic research for each of the clinical trials of the ITN. The ITN is a NIH-funded initiative to facilitate the advancement of immune tolerance-inducing procedures in human clinical practice, towards the development of new and improved treatment and monitoring protocols in kidney, liver and islet transplantation, autoimmune, asthma & allergic diseases. Responsible for designing and implementing a comprehensive mechanistic assay and statistical analysis plan for every ITN clinical trial. Identifies and manages a network of core laboratories in industry (contract research organizations) and academia which run all ITN mechanistic assays. Includes ensuring technical excellence, tracking productivity, setting and managing budgets. Manages the team responsible for building, maintaining and running the databases that receive, clean and house all the ITN mechanistic data. Manages a team of biostatisticians that analyze all ITN mechanistic data in conjunction with clinical information. Responsible for building and implementing a web portal with the architecture behind it to merge clinical and mechanistic data in real time and allow interactive querying, sorting and graphing as well as more complex visualization tools. This is a large collaborative project with multiple 3rd party vendors. Deborah’s team is responsible for the overall design, identification of appropriate vendors, timeline and implementation of this project. Vendor contracts were estimated to be $9.8 million over 4 years Liases with Trial Principal Investigators to interpret clinical/mechanistic data and present it to the scientific community including the ITN Network Steering Committee 2005- 2009 Group Leader, Inflammation Discovery, Roche Palo Alto, LLC. Responsible for leading a group of 5 scientists accountable for Pharmacodynamic (PD) Biomarker Discovery and Novel Drug Discovery. 1. PD Biomarker Discovery to support multiple inflammatory programs. Biomarker discovery for a Phase II oral agent for the treatment of rheumatoid arthritis and other inflammatory diseases PD biomarker representative on 3 late-stage pre-clinical projects consisting of scientists & clinicians representing Discovery Research, PK/PD and Pre-clinical functions. Discovered and developed a PD assay in support of a novel oral agent for the treatment of rheumatoid arthritis and currently managing it’s transition to a clinical CRO to support first-in-man studies. Championed the development of new technologies to measure cytokine release in whole blood assays in a clinical setting. 2. Drug discovery focusing on novel therapies for rheumatoid arthritis & asthma. Championed and co-led a novel drug discovery project targeting a purinergic receptor and key regulator of inflammatory cytokine production. Project accepted into Roche drug discovery portfolio in 2005 and a compound selected for entry into man in Sep 2009. Proposed a new drug discovery project targeting a novel protein kinase and key regulator of T cell and myeloid function for the treatment of rheumatoid arthritis & asthma. Project accepted into the Roche research portfolio in 2007. Currently serving as Project Team Leader, and have coordinated the successful completion of a high throughput screen and the identification of novel chemical scaffolds for the initiation of medicinal chemistry activities. Evaluated multiple RNAi techniques for utility in primary immune cells, both to validate targets and as potential therapeutics Developed multiple in vitro assays of innate and adaptive immunity to assess the relative potential of novel drugs to modulate the immune system. Coordinated a matrix group of 17 biologists to support these assays as part of on-going drug discovery activities. Roche Palo Alto representative to the Roche Functional Genomics Network, a global team focused on implementing novel genomic technologies in drug discovery. Member of Roche Palo Alto Discovery Sciences and Technologies Management Team, a cross-functional leadership team responsible for delivering drug discovery support services to all Roche Palo Alto projects. 2002-2005 Research Scientist II, Genetics & Genomics, Roche Palo Alto, LLC. Led a group of 3 scientists supporting target identification and validation in the area of inflammation and autoimmunity. Implemented siRNA and shRNA technologies in the Genetics & Genomics Group. Numerous genes (e.g. JNK, p38, CD19) were successfully targeted in multiple cell lines and primary human cells. Hired 2 new scientists to build a functional genomics group with the expertise required to carry out in vivo lentiviral shRNA experiments. Team successfully introduced screened shRNAs against CD19 into murine single cell embryos and recovered viable pups. Applied genomic profiling technologies to support the differentiation of novel drug candidates. Used gene microarray profiling, rat genetics and rheumatoid arthritis disease models to identify candidate genes for arthritis susceptibility and severity. This project required extensive liaison with outside collaborators. Member Institutional Animal Care and Use Committee(IACUC) responsible for overseeing all experimental animal protocols and implementing US Federal animal care regulations at Roche Palo Alto. Member of the CNS Therapy Area Management Team, and the Discovery & Sciences Technologies Management Team. Role on these teams was to ensure that the Therapy Areas were aware of, understood and had full access to the technologies within Genetics & Genomics and that they were utilized effectively. One of only 3 people within the Genetics & Genomics organization chosen to participate in the Roche Global Mobilizing Leaders initiative. This initiative was aimed at supporting the development of high-potential leaders in Roche Research. Led the entire Functional Biology Group of 8 FTEs whilst the other team leader was on an extended maternity leave. 1998-2002 Project Leader – OATS (Osteoarthritis Target Search) Department of Arthritis & Inflammation Genomics, Pharmacia Corp. The goals of the OATS project were: Identify specific OA disease progression biomarkers for the clinical evaluation of DMOADS, in particular inhibitors of inducible nitric oxide synthase (iNOS) and matrix metalloproteases (MMPs). Develop the next generation of DMOAD (disease modifying osteoarthritis drugs) targets by identifying the genes/proteins that contribute to the pathogenesis of OA. Accomplishments: Implemented spontaneous and surgical animal models of OA in-house. Namely, the Hartley Guinea pig spontaneous model and a partial meniscal tear surgical model in the rat. Evaluated novel gene profiling technologies e.g. RADE (rapid analysis of differential gene expression). Successful transfer of genomic technology from external partners e.g Laser Capture Micro-dissection. Optimized technologies for transcriptional profiling, in particular, effective RNA extraction from cartilage and bone, RNA amplification and probe preparation for Incyte microarrays. In collaboration with a Bioinformatician analyzed extensive microarray data and developed comprehensive differential gene expression profiles for the rat surgical and guinea pig spontaneous models of OA. Preliminary lists were also compiled for a surgical canine OA model. Mined commercial human databases for genes that are differentially regulated during OA disease and filed provisional patents. Initiated central tissue banking effort to obtain human joint tissues to support multiple target validation and drug discovery projects. Recruited international Consultants to aid in OA Biomarker validation and discovery. Participated in reviews of licensing opportunities related to new target identification Member of Arthritis & Inflammation Leadership Team. The function of this team included the setting of strategic direction for the therapeutic area. Scientific supervision of 4 scientists on the OATs project team as well as line management for 1 other. Additional Contributions Conducted gene expression studies in animal models of rheumatoid arthritis, osteoarthritis and bone disease in support COX-2 and DMOAD drug discovery projects. Developed species-specific reagents to assess the expression of diseaselinked genes in these model systems. Completed Microsoft project training and implemented GANTT charts for OATs project management. Completed Incyte database technology training. Represented Pharmacia Discovery on Project Eagle, a cross-functional initiative to optimize the early drug discovery process. Contributed on a committee of representatives from all business units to design how Pharmacia can best discover, develop and utilize biomarkers. 1995-1998 Postdoctoral Research Fellow Dept. of Neuroscience UPENN School of Medicine, Philadelphia. PA 19104 Principal Investigator: Professor E. Bryan Crenshaw III Responsible for the derivation and characterization of transgenic and knockout mice. One of the knockouts in particular (Brn-4 null mice) had a subtle and unexpected phenotype that was only discovered through vigilant observation of the mice. The predicted neural phenotype was not observed, but the mice showed a 10 decibel reduction in hearing acuity and “head bobbing” that was found to be coincident with changes in the morphology of the inner and middle ear. Ultimately, demonstrated that Brn-4 null mice were phenotypically identical to Slf mice (sex linked fidget mice – a result of X-ray mutagenesis) due to Slf mice having a disrupted optic specific enhancer region for the Brn-4 gene. This investigation involved considerable histology, immunohistochemistry, in situ hybridization, promoter analysis as well as gross pathology. 1994-1995 Postdoctoral Research Fellow Dept. of Craniofacial Development Guy’s and St Thomas’s United Medical and Dental Schools. London, UK Principal Investigator: Professor Paul Sharpe Responsible for the design, construction and use of vectors to analyze the role of Msx (homeobox) genes in the specification of tooth initiation and development using both ectopic expression and targeted gene disruption in mice 1991-1994 Ph.D Graduate Student Dept. of Cell Biology and Experimental Pathology Institute of Cancer Research, London, UK. Advisor: Dr. Trevor Dale Used Northern analysis to demonstrate that some members of the Hox and Msx class homeobox gene families are regulated across developmental boundaries in the mouse mammary gland and in response to hormonal changes. This work involved considerable handling of animals. Tissue culture techniques were used to study gene regulation in vitro. Additionally, cDNA libraries were constructed for differential screening. Further techniques used included: in situ hybridization (both sections and whole mounts), immunohistochemistry and RNase protection assays. 1987-1991 Scientific Officer, Wellcome Diagnostics Dept. Of Molecular Biology Beckenham, Kent. UK Main responsibilities included the cloning and bacterial expression of HIV and Hepatitis C proteins for use in diagnostic assays. This involved establishing new ELISAs for the analysis of the recombinant proteins together with confirmatory Western blot assays. In addition to devising fermentation conditions to maximize the yield of protein for production purposes. Other responsibilities included the training and supervision of junior staff. Professional Activities: Session Chair, Bone and Cartilage Genetics Meeting, Davos, Switzerland, March 2003. Session Chair, Drug Discovery for Inflammatory Diseases, July 2003, Vienna VA. Society Memberships: 2000- 2005 Osteoarthritis Research Society International (OARSI) Publications: Emerson R, Sherwood A, Desmarais C, Malhotra S, Phippard D, Robins H. (2013). Estimating the ratio of CD4+ to CD8+ T cells using high-throughput sequence data. J Immunol Methods. 2013 Feb 18. Du Toit G, Roberts G, Sayre PH, Plaut M, Bahnson HT, Mitchell H, Radulovic S, Chan S, Fox A, Turcanu V, Lack G, Learning Early About Peanut Allergy (LEAP) Study Team. (2013) Identifying infants at high risk of peanut allergy: the Learning Early About Peanut Allergy (LEAP) screening study. J Allergy Clin Immunol. 2013 Jan;131(1):13543. Scadding GW, Calderon MA, Bellido V, Koed GK, Nielsen NC, Lund K, Togias A, Phippard D, Turka LA, Hansel TT, Durham SR, Wurtzen PA. (2012) Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes. J Immunol Methods. 2012 Oct 31;384(1-2):25-32. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, Ahmann A, Rabinovitch A, Aggarwal S, Phippard D, Turka LA, Ehlers MR, Bianchine PJ, Boyle KD, Adah SA, Bluestone JA, Buckner JH, Greenbaum CJ (2012) Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function. Diabetes. 61(9):2340-8. Waubant E, Pelletier D, Mass M, Cohen JA, Kita M, Cross A, Bar-Or A, Vollmer T, Racke M, Stüve O, Schwid S, Goodman A, Kachuck N, Preiningerova J, WeinstockGuttman B, Calabresi PA, Miller A, Mokhtarani M, Iklé D, Murphy S, Kopetskie H, Ding L, Rosenberg E, Spencer C, Zamvil SS; ITN STAyCIS Study Group; ITN020AI Study Management Team (2012) Randomized controlled trial of atorvastatin in clinically isolated syndrome: the STAyCIS study. Neurology. Apr 10;78(15):1171-8. Maecker HT, McCoy JP Jr; FOCIS Human Immunophenotyping Consortium, Amos M, Elliott J, Gaigalas A, Wang L, Aranda R, Banchereau J, Boshoff C, Braun J, Korin Y, Reed E, Cho J, Hafler D, Davis M, Fathman CG, Robinson W, Denny T, Weinhold K, Desai B, Diamond B, Gregersen P, Di Meglio P, Nestle FO, Peakman M, Villanova F, Ferbas J, Field E, Kantor A, Kawabata T, Komocsar W, Lotze M, Nepom J, Ochs H, O'Lone R, Phippard D, Plevy S, Rich S, Roederer M, Rotrosen D, Yeh JH. (2010). A model for harmonizing flow cytometry in clinical trials. Nat. Immunol. Nov;11(11):9758. Erratum in: Nat Immunol. 2010 Nov;11(11):979 Newell KA, Phippard D, Turka LA.(2011). Regulatory cells and cell signatures in clinical transplantation tolerance. Curr Opin Immunol. 2011 Oct;23(5):655-9. Hill, R.J., Dabbagh, K., Phippard, D. Li, C., Suttman, R.T., Welch, M., Papp, E., Song, K.W., Chang, K.C., Leaffer, D., Kim, Y. N., Roberts, R.T., Zabka, T. S., Aud, D., Dal Porto, J., Manning, A. M., Peng, S. L., Goldstein, D.M. & Wong, B. (2008) Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. J. Pharmacol. Exp. Ther. 327(3):610-9. Phippard, D. & Manning A.M. Screening for inhibitors of transcription factors using luciferase reporter genes in transfected cells. Chp 3 in: Methods Mol Biol, (2003) 225: 19-23 Gerstenfeld, L.C., Theide, M., Seibert, K., Mielke, C., Phippard, D. Tewari, S., Svagar, B., Cullinane, D and Einhorn, T.A. (2003) Differential Inhibition of Fracture Healing By Non-Selective and Cyclo-oxygenase-2-selective Non-Steroidal Anti-inflammatory Drugs. Journal of Orthopeadics Research. 21(4):670-5. Phippard, D., Boyd, Y., Reed V., Fisher, G., Masson, W.K, Evans, E.P., Saunders, J.C. and Crenshaw III, E.B. (2000). The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear. Human Molecular Genetics 9(1):79-85. Phippard, D., Lu, L., Lee, D., Saunders, J.C. and Crenshaw III, E.B. (1999). Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear. Journal of Neuroscience 19 (14):5980-9. Phippard, D., Heydemann, A., Lechner, M., Lu, L., Lee, D., Kyin, T. and Crenshaw III, E.B. (1998). Changes in the subcellular localization of the Brn4 gene product precede mesenchymal remodeling of the otic capsule. Hearing Research 120(1-2):77-85. Phippard, D.J., Weber-Hall, S.J., Sharpe, P.T., Naylor, M.S., Jayatalake, H., Maas, R., Woo, I., Roberts-Clark, D., Francis-West, P.H., Liu, Y.H., Maxson, R., Hill, R.E. and Dale, T.C. (1996). Regulation of Msx-1, Msx-2, Bmp-2 and Bmp-4 during foetal and postnatal mammary gland development. Development 122(9):2729-37. Niranjan, B., Buluwela, L., Yant, J., Perusinghe, N., Atherton, A., Phippard, D., Dale, T., Gusterson, B. and Kamalati, T. (1995). HGF/SF: a potent cytokine for mammary growth, morphogenesis and development. Development 121(9):2897-908. Barker, K.T., Martindale, J.E., Mitchell, P.J., Kamalati, T., Page, M.J., Phippard, D.J., Dale, T.C., Gusterson, B.A. and Crompton, M.R. (1995). Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. Oncogene 10(3):569-75. Weber-Hall, S.J., Phippard, D.J., Niemeyer, C.C. and Dale, T.C. (1994). Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation 57(3):205-14. Phippard, D., Sharpe, P. and Dale, T.C. (1994). Msx gene regulation during mouse mammary gland development. In 1994 Hannah Symposium: Intercellular signaling in the mammary gland. Edited by Wilde, C. J., Peaker, M. and Knight, C. H. Plenum Press Riezu-Boj, J.I., Parker, D., Civeira, M.P., Phippard, D., Corbishley, T.P., Camps, J., Castilla, A. and Prieto, J. (1992). Detection of hepatitis C virus antibodies with new recombinant antigens: assessment in chronic liver diseases. Journal of Hepatology 15(3):309-13. Presentations/Abstracts: M.H Shamji, J. A Layhadi, D.K.M Cheung, S.Q Khan, D. Phippard and S.R Durham (2011) Grass Pollen Allergen-induced Surface Expression of CD203c, CD63 and CD107a on CRTH2+ Basophils: Novel Biomarkers for Monitoring Efficacy of Allergenspecific Immunotherapy. World Allergy Congress Accepted 2011 ACR Immunoglobulin Concentrations and Infection Risk Among Patients with ANCAAssociated Vasculitis Treated with Rituximab or Cyclophosphamide. ACR/ARHP Annual Scientific Meeting Stone J, Merkel P, Seo P, Spiera R, Langford C, Hoffman G, Kallenberg C, St. Clair EW, Fessler B, Tchao N, Webber L, Ding L, Sejismundo L, Mieras K, Ikle D, Phippard D, Jepson B, Lail A, Asare A, Lim N, Mueller M, Brunetta P, Allen N, Fervenza F, Geetha D, Keogh K, Kissin E, Monach P, Peikert T, Stegeman C, Ytterberg S, and Specks U for the RAVE-ITN Research Group. Long-term results of the RAVE Trial: Which disease subsets are at greatest risk for disease flare? (2011 ACR abstract selected for oral presentation) S. Alice Long, Srinath Sanda, Jane Buckner, Jennifer Bollyky, Robin Goland, Peter Bianchine, Deborah Phippard, Mario Ehlers and Carla Greenbaum (2011). Rapamycin plus IL-2 combination therapy in subjects with T1D results in a sustained increase in IL-2 responsiveness and a transient decrease in c-peptide levels. Federation of Clinical Immunology Societies (FOCIS) S Feng, J Punch, J Reyes, J Levitsky, G B Klintmalm, M Zimmerman, M Philogene, D Phippard, P Sayre, M DesMarais, H Kopetskie, N Bridges, A Shaked, (2011). Evolution of donor specific alloantibodies (DSA) with immunosuppression (IS) withdrawal among adult liver transplant recipients in ITN030ST. The 2011 Joint International Congress of ILTS, ELITA, & LICAGE S Feng, U Ekong, S Lobritto, A Demetris, P Rosenthal, E Alonso, D Ikle, M Philogene, D Phippard, and N Tchao. (2011) Clinical and Histological Predictors of Operational Tolerance in Pediatric Liver Transplant Recipients. American Transplant Congress (ATC) Noha Lim, Sai Kanaparthi, Suzanne Mertens, Nishant Gopalakrishnan, Zhong Gao, Zhugong Liu, Katarzyna Bourcier, Deborah Phippard, Adam Asare (2010) Automated quality assessments of un-gated flow cytometry FCS files in a clinical trial setting. International Society for the Advancement of Cytometry (ISAC) Mary Carmelle Philogene, Hodan Ali, Adam Asare, Noha Lim, Smita Asare, Kasia Bourcier, Deborah Phippard (2010). Banking RNA for Biomarker Discovery: Assessing RNA Quality and Yield for Long Term Use. Federation of Clinical Immunology Societies (FOCIS) Zhong Gao, Adam Asare, Deborah Phippard, Vincent Carey (2010).Experimental design and quality assurance of high-throughput clinical transplantomics studies: A crucial step toward robust biomarker discovery. International Conference on Transplantomics and Biomarker in organ transplantation Scientific Advisory Board for Conference“Drug Discovery for Inflammatory Diseases” June 2003, Vienna, VA. Chaired workshop “Gene Expression and Proteomic Profiling for Inflammation Research Phippard, D., Sharpe, P. and Dale, T. (1994). Developmental regulation of homeobox genes in the mouse mammary gland. Corbishley, T., Phippard, D., Mason, R., O’Callaghan, S., Doyle, D., Jeffrey, D. and Rodgers, B. (1991). The use of structural antigens and PCR to resolve doubtful anti-HCV antibody results. Phippard, D., Glazebrook, J., Rodgers, B., Garson, J. A., Briggs, M. and Parker, D. (1990). Recombinant ELISA and PCR analysis of PT-NANBH serum samples. Skidmore, S., Elias, E., Neuberger, J., Corbishley, T. and Phippard, D. (1990). Confirmatory testing for anti-hepatitis C. References: Available upon request