Dr. Haas earned his B.S. in biomedical engineering from Duke University in 1991, graduating magna cum laude with distinction. His graduate and medical school training took place at the University of Michigan, where he earned his Ph.D. degree in neuroscience in 1998 and M.D. degree in 1999. At Emory University, he completed his internal medicine internship in 2000, neurology residency at in 2003, and clinical neurophysiology fellowship with an emphasis in epilepsy in 2004. He served as chief resident in neurology for the 2002-2003 medical year.
In 2004, Dr. Haas joined the Vanderbilt University Medical Center faculty as an assistant professor in the neurology department. His clinical focus is epilepsy and he is an attending physician for general neurology and the epilepsy monitoring unit. His research focuses on understanding the molecular mechanisms through which protein degradation pathways regulate physiological synaptic function, and how these pathways contribute to the pathogenesis of neurodevelopmental diseases and epilepsy.
In my laboratory, our research focuses on understanding how targeted protein degradation by the ubiquitin proteasome system (UPS) regulates synaptic function and neuronal excitability in health and in neurodevelopmental disease. A primary mechanism through which synaptic strength is modulated is through changes in the number and composition of ionotropic glutamate and GABAA receptors, which are the principle mediators of fast excitatory and inhibitory neurotransmission in the brain. While there is strong evidence for UPS-mediated degradation of synaptic proteins, its role in modulating neuronal excitability through regulation of glutamate and GABAA receptor function has not been thoroughly explored. We utilize the Drosophila neuromuscular junction synapse to elucidate the time course and mechanisms of UPS-mediated postsynaptic regulation of glutamatergic synaptic function. We utilize cultured rat hippocampal neurons to examine UPS regulation of mammalian AMPA-type glutamate and GABAA receptors.
We strive to translate the basic understanding of neuronal UPS mechanisms into treatments for Angelman syndrome, a devastating neurodevelopmental disease caused by UPS dysfunction. Angelman syndrome (AS) is characterized by severe developmental delay, near complete lack of expressive language development, ataxia of gait and limb movements, refractory epilepsy, and a characteristic happy demeanor. The most common cause of AS is a maternal deletion in the 15q11-13 chromosome region, but mutations in the UBE3A gene found within this region are sufficient to cause all of the phenotypic features of the disease. This gene codes for the Ube3A/E6-AP E3 ubiquitin ligase and is imprinted in the brain, with near complete paternal inactivation leading to maternal-dominated expression in neurons. Mice with knockout of the maternal UBE3A allele show behavioral and physiological similarities to the human AS, including motor incoordination, contextual learning deficits, impaired long-term potentiation, and a propensity for seizures. Epilepsy affects nearly all AS patients, and is frequently intractable, strongly impacting the quality of life for patients and their families. We are utilizing this AS mouse model to understand how Ube3A/E6-AP dysfunction leads to increased neuronal excitability and epilepsy. Also, we use this mouse model to test the effects of therapeutic interventions to restore normal synaptic function and correct neurobehavioral deficits in order to develop AS treatments. Moreover, we expect that these investigations will further the understanding of mechanisms of epileptogenesis and neurodevelopmental disease, providing critical insights into developing new therapies for epilepsy and autism spectrum disorders.
Haas, KF, Broadie, K (2008) Roles of ubiquitination at the synapse, BBA Gene Regulatory Mechanisms, 1779(8) 495-506.
Bianchi, MT, Botzolakis, Haas, KF, Fisher, JL, and Macdonald, RL (2007) Microscopic kinetic determinants of macroscopic currents: insights from coupling and uncoupling of GABAA receptor desensitization and deactivation. Journal of Physiology 584(3) 769-787.
Haas KF, Wooodruff III, Elvin, and Broadie, K (2007) Proteasome Function is Required to Maintain Muscle Cellular Architecture. Biology of the Cell 99(11) 615-626.
Haas, KF, Miller, SL, Friedman, DB, Broadie, K. The ubiquitin-proteasome system postsynaptically regulates glutamatergic synaptic function. Mol Cell Neurosci, 35(1), 64-75, 2007
Kevin F. Haas M.D., Ph.D.
Assistant Professor of Neurology
465 21st Ave South
Nashville, TN 37232