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Hans Bueler
Publisher:管理员LI  Time2016-12-23 View:13

Hans Bueler

PhD, Professor
Phone: 86-0451-86403129
Research Area: Molecular genetics and mechanisms of neurodegeneration

Hans Bueler was trained as a molecular biologist and neuroscientist at the University of Zurich in Switzerland, where he received a M.S. degree in 1988 and Ph.D. in 1992. During his doctoral thesis he 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. After postdoctoral research at the Whitehead Institute for Biomedical Research and Harvard Medical School in Boston in tumor immunotherapy, Dr. Bueler started his own lab back at the University of Zurich as an Assistant Professor of the Swiss National Science Foundation, focusing on the development of viral vectors for gene therapy of Parkinson’s disease and amyotrophic laterals sclerosis. His group demonstrated that AAV-mediated overexpression of the chaperone Hsp70 and the recessive Parkinson’s disease-linked proteins DJ-1 and Parkin confer protection against dopaminergic system degeneration in a mouse model of sporadic Parkinson’s disease. As an Associate Professor at the University of Kentucky Dr. Bueler studied the mechanisms of neuronal dysfunction in animal models of familial Parkinson’s disease. His lab has generated mice lacking PTEN-induced kinase 1 (PINK1), a mitochondrial kinase linked to recessive inherited Parkinson’s disease. PINK1 plays an important role in mitochondrial quality control by regulating the selective degradation of depolarized mitochondria through autophagy, a process referred to as mitophagy. Loss of PINK1 in mice leads to mitochondrial abnormalities, alterations in autophagy, defects in Akt cell survival signaling and age-dependent loss of dopamine. These mechanisms in conjunction with other stress factors may be involved in neurodegeneration. In addition, Dr. Bueler is interested to test the modulatory role of PINK1 on the onset and progression of disease in animal models of other neurodegenerative disorders and to elucidate how loss of PINK1 affects the function of peripheral tissues. Dr. Bueler has joined the School of Life Sciences and Technology of the Harbin Institute of Technology in October 2013.

Research Interests

  • Molecular genetics and cellular mechanisms of neurodegeneration in Parkinson’s disease and related neurodegenerative disorders

  • Identification of novel PINK1 targets/substrates

  • Development of cell-based assays to screen small molecules, drugs and natural compounds with the potential to block neuronal loss

  • Recombinant adeno-associated viral (AAV) vectors for in vivo gene transfer and gene therapy

  • Role of mitochondria and metabolism in neural stem cell function and cell cycle

Molecular Mechanisms and Genetics of Parkinson’s disease


Techniques and Tools in the Lab

  • Generation of knockout/transgenic mice

  • Wide range of molecular biology and biochemistry methods

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

  • Tissue sectioning, immunohistochemistry, histology

  • Brain dissection and catecholamine quantification

  • Production and purification of recombinant adeno-associated viruses (rAAV)

  • AAV-mediated gene transfer to the brain and primary cells/neurons

  • Stereotaxic surgery

  • Light, confocal and electron microscopy

  • Isolation and purification of mitochondria

  • Real-time measurements of mitochondrial respiration and glycolysis in living cells and with isolated mitochondria (Seahorse Flux Analyzer)

Selected Publications

Triplett J.C., Zhang, Z., Sultana, R., Cai, J., Klein, J. B., Bueler, H., Butterfield, D.A. (2015). Quantitative expression proteomics and phosphoproteomics profile of brain from PINK1 knockout mice: insights into mechanisms of familial Parkinson’s disease. J. Neurochem. 133, 750-765.

Sanchez, G., Varaschin, R. K., Bueler, H., Marcogliese, P. C., Park, D. S., Trudeau, L-E. (2014). Unaltered striatal dopamine release levels in young Parkin knockout, Pink1 knockout, DJ-1 knockout, and LRRK2 R1441G transgenic mice. PLOS One 9, e94826.

Ellis, G.I., Zhi, L., Akundi, R.S., Bueler, H. and Marti, F (2013). Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T cell development and function. Eur. J. Immunol, 28 Aug. 2013 DOI: 10.1002/eji.201343571 [Epub ahead of print].

Wang, R., Li, J.J., Diao, S., Kwak, Y-D., Liu, L., Zhi, L., Bueler, H., Bhat, N.R., Williams, R., Park, E.A. and Liao, F.F. (2013). Metabolic stress modulates Alzheimer's b-secretase gene transcription via SIRT1-PPARg-PGC1 i n neurons, Cell Metabolism 17, 685-694.

Akundi, R.S., Zhi, L., Sullivan, P. G. and Bueler, H (2012). Shared and cell type-specific mitochondrial defects and metabolic adaptations i n primary cells from PINK1-deficient mice, Neurodegener Dis, 29 Dec. 2012. DOI: 10.1159/000345689 [Epub ahead of print].

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.

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 i n Pink1-deficient mice. PLOS One 6, e16038.

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.

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

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 i n mice. Mol Ther, 15, 698-704.

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

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

Dong, Z., Ferger, B., Paterna, J.C., Vogel, D., Furler, S., Osinde, M., Feldon, J. and Bueler, H. (2003). Dopamine-dependent neurodegeneration i n rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1. Proc Natl Acad Sci U S A, 100, 12438-12443.

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 i n cultured cells and rat substantia nigra neurons. Gene Ther, 8, 864-873.

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 i n the rat brain. Gene Ther, 7, 1304-1311.

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.

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.

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

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.

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.