Hans Bueler

Email: abp9yz@r.postjobfree.com

Address:

City: Lexington

State: KY

Zip: 40536

Country: USA

Phone: 859-***-****

Skill Level: Any

Salary Range:

Primary Skills/Experience:

Please see attached resume

Educational Background:

High School Dipolma from University of Zurich, Switzerland FL 1/2001 to 11/1992 (Molecular Biology/Neuroscience - Mechanisms of Prion Diseases)

High School Dipolma from University of Zurich, Switzerland FL 1/2001 to 1/2013

Job History / Details:

Education

1992 University of Zurich,

Ph.D. Molecular Biology/Neuroscience - Mechanisms of Prion Diseases

Dissertation (1989-1992), Advisor: Charles Weissmann

Generation and characterization of PrP-deficient mice: a model to study the role of the prion protein (PrP) in transmissible spongiform encephalopathies.

1988 University of Zurich,

Master of Science Molecular Biology - Interferon Gene Regulation/Factor VIII Gene Transfer

Diploma/Master Thesis (1987-1988), Advisor: Charles Weissmann

Part I: Generation of recombinant retroviral vectors for the expression of human coagulation factor VIII in mammalian cells.

Part II: Single point mutations inserted into the virus-responsive element of the human interferon-alpha 1 promoter abolish virus inducibility

Achievements

Summary of the most important research findings. For more details and additional work, please refer to the publication list.

Faculty, University of Kentucky

Demonstrated that loss of Parkin renders Drosophila (flies) more sensitive to redox-active metals and pesticides implicated in the etiology of PD, showing an interacting of recessive PD genes and environmental toxins in PD development (Saini et al., 2010).

Developed and characterized knockout mice for PTEN-induced kinase 1 (PINK1), a mitochondrial kinase linked to recessive familial PD: Established that PINK1 knockout mice develop age-dependent dopamine loss and increased dopamine turnover (key features of PD), which are preceded by calcium-induced mitochondrial permeability transition pore (mPTP) opening and altered expression of innate immunity genes in the brain of PINK1-deficient mice (Akundi et al., 2011). Showed that loss of PINK1 decreases mitochondrial respiratory spare capacity, membrane potential and results in the accumulation of swollen mitochondria with fragmented cristae in primary neurons of PINK1-deficient mice (Akundi et al, Neurodegener Dis, DOI: 10.1159/000345689).

Discovered that PINK1 enhances insulin-like growth factor-induced phosphorylation of the cell survival kinase Akt, thereby controlling the activity of several Akt target proteins implicated in neurodegeneration and/or neuronal health, such as GSK-3beta, FoXO1, mTOR and p70S6 kinase (Akundi et al., 2012). This established an important role for PINK1 in protecting neurons by stimulating Akt, which regulates dopamine neurotransmission and survival of dopamine neurons in several animal models of PD.

Collectively, these studies established a central role of PINK1 in maintaining mitochondrial function and quality control (Bueler, 2009) and in anti-apoptotic Akt cell signaling, providing potential cellular and molecular targets to interfere with PD pathogenesis in the future.

Group Leader, University of Zurich

Engineered and optimized recombinant adeno-associated viral vectors (rAAV) for gene transfer to the nigrostriatal system and peripheral nervous system of rats and mice (Paterna et al., 2000; Glatzel et al., 2000; Furler et al., 2001; Paterna et al., 2002; Paterna et al., 2004)

Designed gene therapy experiments in animal models of Parkinson's disease (PD) based on stereotaxic delivery of rAAV to the nigrostriatal system.

Established that viral overexpression of chaperones (Hsp70) and proteins linked to recessive familial PD (Parkin and DJ-1) confers protection against dopaminergic neuron loss in the MPTP mouse model of sporadic PD, thus demonstrating that familial PD genes protect against oxidative stress and mitochondrial dysfunction implicated in sporadic PD (Dong et al., 2005; Paterna et al., 2007).

Discovered that CDCrel-1, a substrate of the familial PD-linked E3 ligase Parkin, causes dopamine-dependent neuron loss when overexpressed in the substantia nigra of rats. This provided a potential mechanisms for the selective loss of dopaminergic neurons in PD (Dong et al., 2003).

Postdoctoral Fellow, Whitehead Institute for Biomedical Research

Designed and tested genetic and cellular vaccines against selected tumor antigens. Demonstrated efficacy of vaccines against pre-existing tumors in mice and subsequent challenge with tumor cells expressing the corresponding antigens (Bueler and Mulligan, 1996; Klein et al., 2000).

Ph.D. Thesis, University of Zurich

Developed the first prion protein (PrP)-deficient mice and showed that they were resistant to contracting prion disease and failed to replicate the infectious agent. This seminal finding established that PrP is essential for prion disease pathogenesis and prion propagation (Bueler et al., 1992; Bueler et al., 1993; Bueler et al., 1994)

Core Qualifications and Skills

Personal Qualifications

Keen interest in the identification and validation of neurodegenerative mechanisms, and the development of novel targeted therapies to block neuronal loss

Proficient in guiding and mentoring junior/senior scientists to be productive by providing constructive feedback

Exceptional communication skills and professional interaction with other scientists and superiors

Value collaboration with teams of complementing expertise as much as achieving goals on my own

Strong network of collaborators

Proficient in presenting scientific concepts, results and plans to various audiences (experienced speaker and teacher)

Critical thinker with broad knowledge and understanding of biological systems

Can handle multiple tasks and projects simultaneously

High level of organization allows me to plan, execute and evaluate projects effectively

Technical Skills

Generation of knockout/transgenic mice

Production and purification of recombinant adeno-associated viruses (rAAV), adenoviruses and retroviruses

rAAV-mediated gene transfer to the brain and primary cells/neurons.

Stereotaxic surgery

Wide range of molecular biology and biochemistry methods, including genomics and proteomics

Tissue culture and genetic modification of cell lines and primary cells (e.g. cortical neurons)

Isolation and purification of mitochondria. Real-time measurements of mitochondrial respiration and glycolysis in living cells and with isolated mitochondria (XF24 Extracellular Flux Analyzer).

Mouse behavior: Open field, rotarod, amphetamine-induced rotations and locomotion, wheel running, Morris water maze, cylinder test

Other techniques: Tissue sectioning, histology, immunohistochemistry, flow cytometry, purification of T cells, unbiased stereology, catecholamine quantification

Light, confocal and electron microscopy

Other Professional Experience

Ad hoc manuscript reviewer (since 1996)

Molecular Therapy, Gene Therapy, CNS Spectrums, Journal of Neurochemistry, Genes, Brain and Behavior, Journal of Cellular and Molecular Medicine, Experimental Neurology, Apoptosis, Neurobiology of Disease, Cellular and Molecular Life Sciences and PNAS.

Ad hoc research grant reviewer (since 1996)

Swiss National Science Foundation, French National Science Foundation, United Kingdom Parkinson's Disease Society, United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC), French Association of Myopathies and the European Union COST (Cooperation in Science and Technology) Office.

Study section research grant reviewer, US government (since 2010)

RRD6 "Neurodegeneration and Aging" study section of the Veterans Health Administration (VA Department).

Organization of Workshops, Conferences and Public Events

1999-2006

Organization of and participation at public orientations on research in the neurosciences at the University and ETH Zurich (Brain Fairs)

2007

Organizing Committee: Lexington Conference on Translational Neuroscience, April 17-19, 2007.

2011

Organizer and Session Chair: Symposium Genes and Pathways involved in Parkinson's Disease Pathogenesis, 42nd Annual Meeting, American Society for Neurochemistry, St. Louis, 19-23 March 2011.

Awards, Patents, Research Grants

Fellowships

9/1993-9/1995: Postdoctoral fellowship of the Swiss National Science Foundation for advanced scientists

9/1993-9/1995: European Molecular Biology Organization (EMBO) postdoctoral fellowship (relinquished due to double funding)

10/1995-9/1996: Postdoctoral fellowship, Roche Research Foundation (Hoffmann La-Roche, Switzerland)

Awards

11/1992: Jaques de Bedriaga prize awarded for Ph.D. thesis, University of Zurich

1996-2003: START Fellow Award. Non tenure-track group leader position funded by the Swiss National Science Foundation.

2008-2012: Charles T. Wethington Excellence in Research Award, University of Kentucky

2012: Selected abstract and scholarship/travel award to attend the Parkinson's Action Network Leadership Forum, 27-29 February 2012, Washington DC

Patents

1993: Patent (PCT/EP92/02631) for the invention of "Transgenic animals lacking prion proteins"

Research Grants

My work on Parkinson's disease and related projects has been funded by more than 18 grants from various government agencies and private foundations. These included 5 grants from the Swiss National Science Foundation, 3 grants from the National Institutes of Health (NIH), 5 grants from private foundations supporting mechanistic research in Parkinson's disease (USA and Switzerland) and 5 other private foundation grants. The total amount of direct project funding is $4.13 million. More details are available upon request.

Publications

Peer-Reviewed Publications (chronological order)

1. MacDonald, N.J., Kuhl, D., Maguire, D., Naf, D., Gallant, P., Goswamy, A., Hug, H., Bueler, H., Chaturvedi, M., de la Fuente, J. et al. (1990) Different pathways mediate virus inducibility of the human IFN-alpha 1 and IFN-beta genes. Cell, 60, 767-779.

2. Bueler, H., Fischer, M., Lang, Y., Bluethmann, H., Lipp, H.P., DeArmond, S.J., Prusiner, S.B., Aguet, M. and Weissmann, C. (1992) Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature, 356, 577-582.

3. Bueler, H., Aguzzi, A., Sailer, A., Greiner, R.A., Autenried, P., Aguet, M. and Weissmann, C. (1993) Mice devoid of PrP are resistant to scrapie. Cell, 73, 1339-1347.

4. Moser, M., Oesch, B. and Bueler, H. (1993) An anti-prion protein? Nature, 362, 213-214.

5. Weissmann, C., Bueler, H., Fischer, M. and Aguet, M. (1993) Role of the PrP gene in transmissible spongiform encephalopathies. Intervirology, 35, 164-175.

6. Weissmann, C., Bueler, H., Fischer, M., Bluethmann, H. and Aguet, M. (1993) Molecular biology of prion diseases. Dev Biol Stand, 80, 53-54.

7. Weissmann, C., Bueler, H., Sailer, A., Fischer, M., Aguet, M. and Aguzzi, A. (1993) Role of PrP in prion diseases. Br Med Bull, 49, 995-1011.

8. Bueler, H., Raeber, A., Sailer, A., Fischer, M., Aguzzi, A. and Weissmann, C. (1994) High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol Med, 1, 19-30.

9. Sailer, A., Bueler, H., Fischer, M., Aguzzi, A. and Weissmann, C. (1994) No propagation of prions in mice devoid of PrP. Cell, 77, 967-968.

10. Weissmann, C., Bueler, H., Fischer, M., Sailer, A., Aguzzi, A. and Aguet, M. (1994) PrP-deficient mice are resistant to scrapie. Ann N Y Acad Sci, 724, 235-240.

11. Weissmann, C., Bueler, H., Fischer, M., Sauer, A. and Aguet, M. (1994) Susceptibility to scrapie in mice is dependent on PrPC. Philos Trans R Soc Lond B Biol Sci, 343, 431-433.

12. Bueler, H. and Mulligan, R.C. (1996) Induction of antigen-specific tumor immunity by genetic and cellular vaccines against MAGE: enhanced tumor protection by coexpression of granulocyte-macrophage colony-stimulating factor and B7-1. Mol Med, 2, 545-555.

13. Weissmann, C., Fischer, M., Raeber, A., Bueler, H., Sailer, A., Shmerling, D., Rulicke, T., Brandner, S. and Aguzzi, A. (1996) The use of transgenic mice in the investigation of transmissible spongiform encephalopathies. Int J Exp Pathol, 77, 283-293.

14. Weissmann, C., Fischer, M., Raeber, A., Bueler, H., Sailer, A., Shmerling, D., Rulicke, T., Brandner, S. and Aguzzi, A. (1996) The role of PrP in pathogenesis of experimental scrapie. Cold Spring Harb Symp Quant Biol, 61, 511-522.

15. Weissmann, C., Fischer, M., Raeber, A., Bueler, H., Sailer, A., Shmerling, D., Rulicke, T., Brandner, S. and Aguzzi, A. (1998) The use of transgenic mice in the investigation of transmissible spongiform encephalopathies. Rev Sci Tech, 17, 278-290.

16. Bueler, H. (1999) Adeno-associated viral vectors for gene transfer and gene therapy. Biol Chem, 380, 613-622.

17. Azzouz, M., Hottinger, A., Paterna, J.C., Zurn, A.D., Aebischer, P. and Bueler, H. (2000) Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2. Hum Mol Genet, 9, 803-811.

18. Glatzel, M., Flechsig, E., Navarro, B., Klein, M.A., Paterna, J.C., Bueler, H. and Aguzzi, A. (2000) Adenoviral and adeno-associated viral transfer of genes to the peripheral nervous system. Proc Natl Acad Sci U S A, 97, 442-447.

19. Klein, C., Bueler, H. and Mulligan, R.C. (2000) Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines. J Exp Med, 191, 1699-1708.

20. Paterna, J.C., Moccetti, T., Mura, A., Feldon, J. and Bueler, H. (2000) Influence of promoter and WHV post-transcriptional regulatory element on AAV-mediated transgene expression in the rat brain. Gene Ther, 7, 1304-1311.

21. Ehrengruber, M.U., Hennou, S., Bueler, H., Naim, H.Y., Deglon, N. and Lundstrom, K. (2001) Gene transfer into neurons from hippocampal slices: comparison of recombinant Semliki Forest Virus, adenovirus, adeno-associated virus, lentivirus, and measles virus. Mol Cell Neurosci, 17, 855-871.

22. Furler, S., Paterna, J.C., Weibel, M. and Bueler, H. (2001) Recombinant AAV vectors containing the foot and mouth disease virus 2A sequence confer efficient bicistronic gene expression in cultured cells and rat substantia nigra neurons. Gene Ther, 8, 864-873.

23. Karkkainen, M.J., Saaristo, A., Jussila, L., Karila, K.A., Lawrence, E.C., Pajusola, K., Bueler, H., Eichmann, A., Kauppinen, R., Kettunen, M.I. et al. (2001) A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A, 98, 126**-*****.

24. Dong, Z., Ferger, B., Feldon, J. and Bueler, H. (2002) Overexpression of Parkinson's disease-associated alpha-synucleinA53T by recombinant adeno-associated virus in mice does not increase the vulnerability of dopaminergic neurons to MPTP. J Neurobiol, 53, 1-10.

25. Pajusola, K., Gruchala, M., Joch, H., Luscher, T.F., Yla-Herttuala, S. and Bueler, H. (2002) Cell-type-specific characteristics modulate the transduction efficiency of adeno-associated virus type 2 and restrain infection of endothelial cells. J Virol, 76, 115**-*****.

26. Paterna, J.C. and Bueler, H. (2002) Recombinant adeno-associated virus vector design and gene expression in the mammalian brain. Methods, 28, 208-218.

27. Saaristo, A., Veikkola, T., Enholm, B., Hytonen, M., Arola, J., Pajusola, K., Turunen, P., Jeltsch, M., Karkkainen, M.J., Kerjaschki, D., Bueler, H., Yla-Herttuala, S. and Alitalo, K. (2002) Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. FASEB J, 16, 1041-1049.

28. Saaristo, A., Veikkola, T., Tammela, T., Enholm, B., Karkkainen, M.J., Pajusola, K., Bueler, H., Yla-Herttuala, S. and Alitalo, K. (2002) Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med, 196, 719-730.

29. Dong, Z., Ferger, B., Paterna, J.C., Vogel, D., Furler, S., Osinde, M., Feldon, J. and Bueler, H. (2003) Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A, 100, 124**-*****.

30. Jalkanen, J., Leppanen, P., Pajusola, K., Narvanen, O., Mahonen, A., Vahakangas, E., Greaves, D.R., Bueler, H. and Yla-Herttuala, S. (2003) Adeno-associated virus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor reduces atherosclerotic lesion formation in LDL receptor knockout mice. Mol Ther, 8, 903-910.

31. Vassalli, G., Bueler, H., Dudler, J., von Segesser, L.K. and Kappenberger, L. (2003) Adeno-associated virus (AAV) vectors achieve prolonged transgene expression in mouse myocardium and arteries in vivo: a comparative study with adenovirus vectors. Int J Cardiol, 90, 229-238.

32. Fraefel, C., Bittermann, A.G., Bueler, H., Heid, I., Bachi, T. and Ackermann, M. (2004) Spatial and temporal organization of adeno-associated virus DNA replication in live cells. J Virol, 78, 389-398.

33. Gruchala, M., Bhardwaj, S., Pajusola, K., Roy, H., Rissanen, T.T., Kokina, I., Kholova, I., Markkanen, J.E., Rutanen, J., Heikura, T., Alitalo, K., Bueler, H. and Yla-Herttuala, S. (2004) Gene transfer into rabbit arteries with adeno-associated virus and adenovirus vectors. J Gene Med, 6, 545-554.

34. Paterna, J.C., Feldon, J. and Bueler, H. (2004) Transduction profiles of recombinant adeno-associated virus vectors derived from serotypes 2 and 5 in the nigrostriatal system of rats. J Virol, 78, 6808-6817.

35. Weissmann, C. and Bueler, H. (2004) A mouse to remember. Cell, 116, S111-113, 112 p following S113.

36. Dong, Z., Wolfer, D.P., Lipp, H.P. and Bueler, H. (2005) Hsp70 gene transfer by adeno-associated virus inhibits MPTP-induced nigrostriatal degeneration in the mouse model of Parkinson disease. Mol Ther, 11, 80-88.

37. Bueler, H. (2006) Molecular mechanisms and genetics of Parkinson disease. Pharm Unserer Zeit, 35, 198-203.

38. Paterna, J.C., Leng, A., Weber, E., Feldon, J. and Bueler, H. (2007) DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice. Mol Ther, 15, 698-704.

39. Pietropaolo, S., Paterna, J.C., Bueler, H., Feldon, J. and Yee, B.K. (2007) Bidirectional changes in water-maze learning following recombinant adenovirus-associated viral vector (rAAV)-mediated brain-derived neurotrophic factor expression in the rat hippocampus. Behav Pharmacol, 18, 533-547.

40. Zach, S., Bueler, H., Hengerer, B. and Gillardon, F. (2007) Predominant neuritic pathology induced by viral overexpression of alpha-synuclein in cell culture. Cell Mol Neurobiol, 27, 505-515.

41. Bueler, H. (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp Neurol, 218, 235-246 (Special Issue: Mitochondria and Neurodegeneration)

42. Sulg, M., Kirjavainen, A., Pajusola, K., Bueler, H., Ylikoski, J., Laiho, M. and Pirvola, U. (2010). Differential sensitivity of the inner ear sensory cell populations to forced cell cycle re-entry and p53 induction. J Neurochem, 112, 1513-1526.

43. Bueler, H. (2010) Mitochondrial dynamics, cell death and the pathogenesis of Parkinson's disease. Apoptosis 15, 1336-1353 (Special Issue: Apoptosis in the Aging Brain).

44. Saini, N., Oelhafen, S., Hua, H., Georgiev, O., Schaffner, W. and Bueler, H. (2010) Extended lifespan of Drosophila parkin mutants through sequestration of redox-active metals and enhancement of anti-oxidative pathways. Neurobiol Dis 40, 82-92.

45. Akundi, R. S., Huang, Z., Eason, J., Pandya, J. D., Zhi, L., Cass, W. A., Sullivan, P. G. and Bueler, H. (2011). Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLOS One 6, e16038.

46. Akundi, R. S., Zhi, L. and Bueler, H. (2012). PINK1 enhances insulin-like growth factor-1-dependent Akt signaling and protection against apoptosis, Neurobiol Dis 45, 469-478.

47. Akundi, R.S., Zhi, L., Sullivan, P. G. and Bueler, H. Shared and cell type-specific mitochondrial defects and metabolic adaptations in primary cells from PINK1-deficient mice, Neurodegener Dis, published online 29 December 2012 (DOI:10.1159/000345689)

Book Chapters

1. Weissmann, C., Bueler, H., Fischer, M., and Aguet, M. (1993). The PrP-less mouse: a tool for prion research. In "Transgenic Animals as Model Systems for Human Diseases". Schering Foundation Workshop 6 (E. F. Wagner, F. Theuring, eds.). Springer Verlag, pp. 39-56.

Conference Presentations

Talks at National Conferences

10/1999

Swiss National Science Foundation, Annual Meeting of the National Research Priority Somatic Gene Therapy NRP37, Fribourg, Switzerland: Increased motor neuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2.

10/1999

Swiss National Science Foundation, Annual Meeting of the National Research Priority Somatic Gene Therapy NRP37, Fribourg, Switzerland: Effects of promoter and viral post-transcriptional regulatory elements on adeno-associated virus-mediated transgene expression in the brain.

3/2004

Bi-annual Meeting of the Swiss Society for Neuropathology, St. Moritz, Switzerland: Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1.

3/2006

Bi-annual Meeting of the Swiss Society for Neuropathology, St. Moritz, Switzerland: DJ-1 and Parkin modulate dopamine neurotransmission and protect against nigral dopaminergic neuron loss in a mouse model of sporadic Parkinson's disease.

3/2011

American Society for Neurochemistry 42nd Annual Meeting, St. Louis, MO: PINK1 deficiency results in abnormal dopamine homeostasis and affects innate immune and cell survival signaling.

2/2012

Parkinson's Action Network Leadership Forum: Neurological, cell signaling and metabolic defects in PINK-deficient mice support a link between diabetes and early-onset Parkinson's disease. 27-29 February 2012, Washington, DC.

Talks at International Conferences

6/2002

American Society of Gene Therapy 5th Annual Meeting, Boston, MA: Recombinant AAV-mediated expression of the Parkin target protein CDCrel-1 induces dopaminergic neurodegeneration and dopamine loss in rats: Implications for the pathogenesis of autosomal-recessive juvenile Parkinsonism.

3/2007

British Society for Gene Therapy 4th Annual Conference, Warwick, England: DJ-1 and Parkin modulate dopamine-dependent behavior and inhibit MPTP-induced nigral dopamine neuron loss in mice.

Poster Presentations

In the interest of brevity poster abstracts have not been listed but are available upon request.

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