Dr. Bruce L. Tempel |
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University of Washington School of Medicine Otolaryngolgy-HNS and Pharmacology The V.M. Bloedel Hearing Research Center ProfessorAppointed: 2001 |  |
Mailing AddressUniversity of Washington School of Medicine Depts. of Otolaryngology and Pharmacology V.M. Bloedel Hearing Research Center Box 357923 Seattle, Washington 98195-7923United States | Contact InformationPhone: (206) 616-4693 Fax: (206) 616-1828 bltempel@u.washington.edu http://depts.washington.edu/tempelab/ |
Qualifications
Ph.D., Princeton University, 1983.
M.A., Princeton University, 1980.
B.S., Pacific Lutheran University, 1978.
Expertise and Research Interests
Neurogenetics of Auditory Function
Research in the Tempel lab is aimed at understanding various components of the complex biological process of hearing, both in the cochlea where sounds are transduced by hair cells and in the central nervous system where sounds are encoded by action potentials transmitted to the auditory cortex. We use the power of genetics to unravel this complexity, leaping from behavior to molecules by studying deaf mouse mutants and human families with heritable forms of hearing loss. These "patients" allow us to identify specific genes contributing to the process of hearing. Detailed studies on each gene provide us with information on how hearing happens and how hearing loss might be ameliorated.
Genetics of Hearing Loss
Approximately one in every thousand babies is born with significant hearing loss; at least half of these cases are due to an inherited genetic condition. As people age, noise-induced and/or age-related hearing loss causes significant hearing loss and interferes with speech communication in roughly 50% of the U.S. population at retirement age. The effects of hearing loss have both economic and interpersonal consequences for affected individuals and their families.
In 1998 we discovered that the deafwaddler mouse was deaf because of a mutation in a calcium ion pump, PMCA2 (Street et al., 1998). Recent work has shown that even slight reductions in activity of this pump causes high frequency hearing loss in mice that is very similar to age-related hearing loss, or presbycusis, in humans (McCullough and Tempel, 2004). Ongoing studies are aimed at identifying ways to prevent hearing loss in deafwaddler mice using pharmacological or gene-therapy approaches.
In collaboration with colleagues at Harvard University, we are analyzing strains of mice that are uniquely resistant to noise exposure. We use quantitative trait locus (QTL) mapping techniques to identify chromosomal regions that make these mice resistant to noise. We also use DNA micro-array techniques to identify genes that are differentially expressed between resistant and non-resistant strains of mice. Genes that are differentially expressed AND map to the QTL regions are particularly good candidates for further studies. Homologous genes in humans are likely to contribute to noise resistance in man.
Auditory Signal Encoding
The ability to localize the source, intensity and pitch of a sound is critical for locating predators, enjoying music and having a casual conversation. These higher order auditory functions require that sounds be encoded by the nervous system and transmitted as action potentials with high temporal precision and fidelity. Similar requirements for rapid, precise temporal encoding are needed for fine muscle control in the descending motor pathway. To meet these demands, the nervous system has developed a number of specializations including the use of specific voltage-gated potassium channels that open quickly and prevent extra action potentials that would degrade the encoded information. These channels are localized to specific parts of the neurons where action potential are initiated and propagated. We have studied two of these genes - Kv1.1 and Kv1.2 - by making knockout mice that lack each of the genes and then analyzing the effect on behavior and transmission. We find that deletion of either of these two genes causes epilepsy in the knockout mice. When studied using electrophysiology, action potential transmission is altered in auditory nuclei of mice lacking Kv1.1, whether in tissue slices (Brew et al., 2003) or in vivo (Kopp-Scheinpflug et al., 2003).
We reported in 2001 that deafness in quivering mice was caused by mutations in a structural gene, spectrin beta 4, which anchors sodium channels at axon initial segments and at nodes of Ranvier (Parkinson et al., 2001). We hypothesize that action potential transmission is again altered in auditory nuclei but in this mutant because the balance between excitatory sodium channels and inhibitory potassium channels is disrupted. Ongoing studies on an allelic series of quivering mice are aimed at identifying the critical sites of action for the spectrin beta 4 gene.
In summary, studies in our lab use genetics as a starting point. That each of the mutant mouse strains (or human families) have a phenotype tells us that the altered gene is important. The complex structure of the auditory system and it's demand for fast and precise encoding is the likely reason why there are a large number of genes, mutation of which causes hearing loss. The fact that auditory malfunctions are not lethal to the organism makes genetic analysis of hearing loss a particularly useful way to probe the biological basis of this elegantly evolved sensory system.
Research in the Tempel lab is aimed at understanding various components of the complex biological process of hearing, both in the cochlea where sounds are transduced by hair cells and in the central nervous system where sounds are encoded by action potentials transmitted to the auditory cortex. We use the power of genetics to unravel this complexity, leaping from behavior to molecules by studying deaf mouse mutants and human families with heritable forms of hearing loss. These "patients" allow us to identify specific genes contributing to the process of hearing. Detailed studies on each gene provide us with information on how hearing happens and how hearing loss might be ameliorated.
Genetics of Hearing Loss
Approximately one in every thousand babies is born with significant hearing loss; at least half of these cases are due to an inherited genetic condition. As people age, noise-induced and/or age-related hearing loss causes significant hearing loss and interferes with speech communication in roughly 50% of the U.S. population at retirement age. The effects of hearing loss have both economic and interpersonal consequences for affected individuals and their families.
In 1998 we discovered that the deafwaddler mouse was deaf because of a mutation in a calcium ion pump, PMCA2 (Street et al., 1998). Recent work has shown that even slight reductions in activity of this pump causes high frequency hearing loss in mice that is very similar to age-related hearing loss, or presbycusis, in humans (McCullough and Tempel, 2004). Ongoing studies are aimed at identifying ways to prevent hearing loss in deafwaddler mice using pharmacological or gene-therapy approaches.
In collaboration with colleagues at Harvard University, we are analyzing strains of mice that are uniquely resistant to noise exposure. We use quantitative trait locus (QTL) mapping techniques to identify chromosomal regions that make these mice resistant to noise. We also use DNA micro-array techniques to identify genes that are differentially expressed between resistant and non-resistant strains of mice. Genes that are differentially expressed AND map to the QTL regions are particularly good candidates for further studies. Homologous genes in humans are likely to contribute to noise resistance in man.
Auditory Signal Encoding
The ability to localize the source, intensity and pitch of a sound is critical for locating predators, enjoying music and having a casual conversation. These higher order auditory functions require that sounds be encoded by the nervous system and transmitted as action potentials with high temporal precision and fidelity. Similar requirements for rapid, precise temporal encoding are needed for fine muscle control in the descending motor pathway. To meet these demands, the nervous system has developed a number of specializations including the use of specific voltage-gated potassium channels that open quickly and prevent extra action potentials that would degrade the encoded information. These channels are localized to specific parts of the neurons where action potential are initiated and propagated. We have studied two of these genes - Kv1.1 and Kv1.2 - by making knockout mice that lack each of the genes and then analyzing the effect on behavior and transmission. We find that deletion of either of these two genes causes epilepsy in the knockout mice. When studied using electrophysiology, action potential transmission is altered in auditory nuclei of mice lacking Kv1.1, whether in tissue slices (Brew et al., 2003) or in vivo (Kopp-Scheinpflug et al., 2003).
We reported in 2001 that deafness in quivering mice was caused by mutations in a structural gene, spectrin beta 4, which anchors sodium channels at axon initial segments and at nodes of Ranvier (Parkinson et al., 2001). We hypothesize that action potential transmission is again altered in auditory nuclei but in this mutant because the balance between excitatory sodium channels and inhibitory potassium channels is disrupted. Ongoing studies on an allelic series of quivering mice are aimed at identifying the critical sites of action for the spectrin beta 4 gene.
In summary, studies in our lab use genetics as a starting point. That each of the mutant mouse strains (or human families) have a phenotype tells us that the altered gene is important. The complex structure of the auditory system and it's demand for fast and precise encoding is the likely reason why there are a large number of genes, mutation of which causes hearing loss. The fact that auditory malfunctions are not lethal to the organism makes genetic analysis of hearing loss a particularly useful way to probe the biological basis of this elegantly evolved sensory system.
Future Research
One future focus is on identifying the genes that contribute to noise resistance. We have completed a quantitative trait locus (QTL) map that shows three chromosomes with significant LOD score peaks. We are currently evaluating candidate genes using expression profiling on arrays, ancestral SNP analysis and direct sequence comparisons between resistant and non-resistant strains.
A second focus is on the role of Atp2b2, the deafwaddler gene, as a modifier gene that interacts with other hearing loss loci in both mice and humans. We are also studying the role of Atp2b2 in age-related hearing loss (ARHL) as well as in noise-induced hearing loss (NIHL) using an allelic series of mutants to give varying dosages of gene function.
A second focus is on the role of Atp2b2, the deafwaddler gene, as a modifier gene that interacts with other hearing loss loci in both mice and humans. We are also studying the role of Atp2b2 in age-related hearing loss (ARHL) as well as in noise-induced hearing loss (NIHL) using an allelic series of mutants to give varying dosages of gene function.
Keywords
COS Keywords:
Audiology, Deafness, Diseases and Disorders, Epilepsy, Genes, Genetics, Hearing, Human Learning and Memory, Immunochemistry, Membranes, Molecular Biology, Mutagenesis, Pharmacology.Additional Terms:
Auditory System, Genetics, Hearing loss and Deafness, Molecular Genetics, Plasma Membrane Ca-ATPase Genes, Potassium (Kv) Channel Genes, Signal Encoding.Languages
(Reading, Writing, Speaking)
German: (Functional, Basic, Functional)
Memberships
American Association for the Advancement of Science
Association for Research in Otolaryngology
International Mammalian Genome Society
Society for Neuroscience
Honors and Awards
2004, Visiting Professorship in Biomedical Sciences,
University of Queensland, Australia
2000-2005,
NIDCD Board of Scientific Couselors,
National Institutes of Health (NIH)
1991-1994,
Klingenstein Fellow in the Neurosciences,
The Esther A. & Joseph Klingenstein Fund,
University of Washington
1984-1986,
ACS Postdoctoral Fellowship,
American Cancer Society,
University of California San Francisco
1983, Donald Lindsley Prize,
Society for Neurosciences
1978-1982,
NSF Predoctoral Fellowship,
National Science Foundation (NSF),
Princeton University,
Neuroscience
Previous Positions
1995-2001, Associate Professor,
University of Washington,
School of Medicine,
Otolaryngology--Head and Neck Surgery
1994-2001, Associate Professor,
University of Washington,
School of Medicine,
Pharmacology
1988-1994, Assistant Professor,
University of Washington,
School of Medicine,
Medicine
1988-1994, Assistant Professor,
University of Washington,
School of Medicine,
Pharmacology
1984-1988, Post-doctoral Fellow,
University of California, San Francisco,
Howard Hughes Medical Institute
Funding Received
- National Institutes of Health (NIH): Genetics of Noise Resistance, $250,000 direct cost, 2003 to 2008.
- National Institutes of Health (NIH): U.W. Core for Communication Research, $100,000 direct cost, 2000 to 2010.
- National Institutes of Health (NIH): Auditory Neurogenetics, $250,000 direct cost, 1995 to 2007.
Publications
- Duncan, J.L., Yang, H., Doan, T., Silverstein, R.S., Murphy, G.J., Nune, G., Liu, X., Copenhagen, D., Tempel, B.L, Rieke, F. and Krizaj, D. (2006) Scotopic visual signaling in the mouse reina is modulated by high affinity membrane calcium extrusion, J. Neurosci., 26, 7201-7211.
- Silverstein RS, Tempel BL (2006) Atp2b2, encoding plasma membrane ca(2+)-atpase type 2, exhibits tissue-specific first exon usage in hair cells, neurons, and mammary glands of mice, Neuroscience, 141, 245-257.
- Gittleman JX, Tempel BL (2006) Kv1.1 containing channels are critical for temporal precision during spike initiation, J. Neurophysiol.
- Keogh BP, Cordes D, Stanberry L, Figler BD, Robbins CA, Tempel BL, Green CG, Emmi A, Maravilla KM, Schwartzkroin PA (Aug-Sep 2005) BOLD-fMRI of PTZ-induced seizures in rats, Epilepsy Research, 66 (1-3), 75-90
- McCullough BJ, Tempel BL (Sep 2004) Haplo-insufficiency revealed in deafwaddler mice when tested for hearing loss and ataxia, Hearing Research, 195 (1-2), 90-102
- Wood JD, Muchinsky SJ, Filoteo AG, Penniston JT, Tempel BL (Jun 2004) Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance, JARO, 5 (2), 99-110
- Lu Y, Monsivais P, Tempel BL, Rubel EW (Feb 2004) Activity-dependent regulation of the potassium channel subunits Kv1.1 and Kv3.1, Journal of Comparative Neurology, 470 (1), 93-106
- Lopantsev V, Tempel BL, Schwartzkroin PA (Dec 2003) Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1, Epilepsia, 44 (12), 1506-12
- Kopp-Scheinpflug C, Fuchs K, Lippe WR, Tempel BL, Rubsamen R (Oct 2003) Decreased temporal precision of auditory signaling in Kcna1-null mice: an electrophysiological study in vivo, J. Neurosci., 23 (27), 9199-207
- Rosowski JJ, Brinsko KM, Tempel BI, Kujawa SG (Sep 2003) The aging of the middle ear in 129S6/SvEvTac and CBA/CaJ mice: measurements of umbo velocity, hearing function, and the incidence of pathology, JARO, 4 (3), 371-83
- Brew HM, Hallows JL, Tempel BL (Apr 2003) Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1, J. Physiol., 548 (Pt 1), 1-20
- Street VA, Goldy JD, Golden AS, Tempel BL, Bird TD, Chance PF, Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies, American Journal of Human Genetics, 70(1), 244-50, January 2002
- Parkinson NJ, Olsson CL, Hallows JL, McKee-Johnson J, Keogh BP, Noben-Trauth K, Kujawa SG, Tempel BL, Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice, Nature Genetics, 29(1), 61-5, September 2001
- Frankel WN, Taylor L, Beyer B, Tempel BL, White HS, Electroconvulsive thresholds of inbred mouse strains, Genomics, 74(3), 306-12, June 2001
- van Brederode JF, Rho JM, Cerne R, Tempel BL, Spain WJ, Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice, Neuroscience, 103(4), 921-9, 2001
- Konrad-Martin D, Norton SJ, Mascher KE, Tempel BL, Effects of PMCA2 mutation on DPOAE amplitudes and latencies in deafwaddler mice, Hearing Research, 151(1-2), 205-220, Jan 2001
- Grigg JJ, Brew HM, Tempel BL, Differential expression of voltage-gated potassium channel genes in auditory nuclei of the mouse brainstem., Hearing Research, 140(1-2), 77-90, 2000
- Rho JM, Szot P, Tempel BL, Schwartzkroin PA, Developmental seizure susceptibility of kv1.1 potassium channel knockout mice., Developmental Neuroscience, 21(3-5), 320-7, November 1999
- Hallows JL, Tempel BL, Expression of Kv1.1, a Shaker-like potassium channel, is temporally regulated in embryonic neurons and glia, Journal of Neuroscience, 18(15), 5682-91, August 1998
- Redell JB, Tempel BL, Multiple promoter elements interact to control the transcription of the potassium channel gene, KCNJ2, Journal of Biological Chemistry, 273(35), 22807-18, August 1998
- Street VA, McKee-Johnson JW, Fonseca RC, Tempel BL, Noben-Trauth K, Mutations in a plasma membrane Ca2 -ATPase gene cause deafness in deafwaddler mice, Nature Genetics, 19(4), 390-4, August 1998
- Allen ML, Koh DS, Tempel BL, Cyclic AMP regulates potassium channel expression in C6 glioma by destabilizing Kv1.1 mRNA, Proceedings of the National Academy of Sciences (USA), 95(13), 7693-8, June 1998
- McKee-Johnson JW, Street VA, Erford SK, Robinson LC, Tempel BL, Physical and genetic maps of the deafwaddler region on distal mouse Chr 6, Genomics, 49(3), 371-7, May 1998
- Smart SL, Lopantsev V, Zhang CL, Robbins CA, Wang H, Chiu SY, Schwartzkroin PA, Messing A, Tempel BL, Deletion of the K(V)1.1 potassium channel causes epilepsy in mice, Neuron, 20(4), 809-19, April 1998
- Smart SL, Bosma MM, Tempel BL, Identification of the delayed rectifier potassium channel, Kv1.6, in cultured astrocytes, Glia, 20(2), 127-34, June 1997
- Street VA, Bosma MM, Demas VP, Regan MR, Lin DD, Robinson LC, Agnew WS, Tempel BL, The type 1 inositol 1,4,5-trisphosphate receptor gene is altered in the opisthotonos mouse, Journal of Neuroscience, 17(2), 635-45, January 1997
- Wang H, Allen M L, Grigg J J, Noebels J L, Tempel B L, Hypomyelination alters K+ channel expression in mouse mutants shiverer and Trembler., Neuron, 15(6), 1337-47, December 1995
- Street V A, Robinson L C, Erford S K, Tempel B L, Molecular genetic analysis of distal mouse chromosome 6 defines gene order and positions of the deafwaddler and opisthotonos mutations., Genomics, 29(1), 123-30, 1 Sep 1995
- Tempel B L, Hopkins W F, Potassium channels at nodes of Ranvier: a role in disease?, Society of General Physiologists Series, 50, 41-52, 1995
- Hopkins W F, Allen M L, Houamed K M, Tempel B L, Properties of voltage-gated K+ currents expressed in Xenopus oocytes by mKv1.1, mKv1.2 and their heteromultimers as revealed by mutagenesis of the dendrotoxin-binding site in mKv1.1., Pflügers archiv. European Journal of Physiology, 428(3-4), 382-90, October 1994
- Wang H, Kunkel D D, Schwartzkroin P A, Tempel B L, Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain., Journal of Neuroscience, 14(8), 4588-99, August 1994
- Lock L F, Gilbert D J, Street V A, Migeon M B, Jenkins N A, Copeland N G, Tempel B L, Voltage-gated potassium channel genes are clustered in paralogous regions of the mouse genome., Genomics, 20(3), 354-62, April 1994
- Hopkins W F, Demas V, Tempel B L, Both N- and C-terminal regions contribute to the assembly and functional expression of homo- and heteromultimeric voltage-gated K+ channels., Journal of Neuroscience, 14(3 Pt 1), 1385-93, March 1994
- Bosma M M, Allen M L, Martin T M, Tempel B L, PKA-dependent regulation of mKv1.1, a mouse Shaker-like potassium channel gene, when stably expressed in CHO cells., Journal of Neuroscience, 13(12), 5242-50, December 1993
- Wang H, Kunkel D D, Martin T M, Schwartzkroin P A, Tempel B L, Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons., Nature, 365(6441), 75-9, 2 Sep 1993
- Newland C F, Adelman J P, Tempel B L, Almers W, Repulsion between tetraethylammonium ions in cloned voltage-gated potassium channels., Neuron, 8(5), 975-82, May 1992
- Migeon M B, Street V A, Demas V P, Tempel B L, Cloning, sequence and chromosomal localization of MK6, a murine potassium channel gene., Epilepsy research. Supplement, 9, 173-80; discussion 1, 1992
- Rehm H, Tempel B L, Voltage-gated K+ channels of the mammalian brain., Faseb Journal, 5(2), 164-70, February 1991
- Chandy K G, Williams C B, Spencer R H, Aguilar B A, Ghanshani S, Tempel B L, Gutman G A, A family of three mouse potassium channel genes with intronless coding regions., Science, 247(4945), 973-5, 23 Feb 1990
- Rehm H, Newitt RA, Tempel BL, Immunological evidence for a relationship between the dendrotoxin-binding protein and the mammalian homologue of the Drosophila Shaker K channel, Febs Letters, 249(2), 224-8, June 1989
- Tempel BL, Jan YN, Jan LY, Cloning of a probable potassium channel gene from mouse brain, Nature, 332(6167), 837-9, April 1988
- Schwarz TL, Tempel BL, Papazian DM, Jan YN, Jan LY, Multiple potassium-channel components are produced by alternative splicing at the Shaker locus in Drosophila [published erratum appears in Nature 1988 Apr 21;332(6166):740], Nature, 331(6152), 137-42, January 1988
- Timpe LC, Schwarz TL, Tempel BL, Papazian DM, Jan YN, Jan LY, Expression of functional potassium channels from Shaker cDNA in Xenopus oocytes, Nature, 331(6152), 143-5, January 1988
- Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan LY, Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila, Science, 237(4816), 749-53, August 1987
- Tempel BL, Papazian DM, Schwarz TL, Jan YN, Jan LY, Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila, Science, 237(4816), 770-5, August 1987
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