Mechanisms of epileptogenesis: Gene therapy by neuropeptides, neurotrophic factors and optogenetics
Principal investigator; Kokaia, Merab, Professor, PhD
Epilepsy has recently attracted a broad attention from European Community. In October 2011, the European Parliament has signed "The Written Declaration on Epilepsy" document, which defines this field as a prioritized research area on the European arena. Epilepsies are a family of devastating multifactorial chronic neurological disorders characterized by recurrent seizures, affecting at least 50 million people worldwide, among which 6 million people live in Europe. About 60 000 of these live in Sweden. According to WHO, the consequences of epilepsy in Europe costs 20 billion euros per year. Epilepsies and associated comorbidities pose a significant burden on the quality of life of affected individuals and their families. Available pharmacological treatments are only symptomatic, have side effects and fail to adequately control seizures in a third of patients. Surgical intervention is a last resort, but only for limited number of pharmacoresistant patients.
We explore the role of neuropeptides and neurotrophic factors in modulation of excitatory and inhibitory synaptic transmission and epileptogensis in the brain. We use respective knock-out and overexpressing mice in combination with in vivo epilepsy models (kindling, status epilepsitcus) and in vitro approaches (patch-clamp in brain slices). One of the specific aims of this research line is to use both direct and indirect targeted gene transfer of neuropeptides and neurotrophic factors into the different brain regions to investigate mechanistic aspects of their action on synaptic transmission and epileptogensis. Using optogenetic approach, we also explore mechanisms of epileptogenesis and seizures, and develop alternative treatment strategies for epilepsy.
This research will help in better understanding of the mechanisms for epileptogenesis and might lead to development of new gene therapy-based strategies for epilepsy treatment.
Link to project homepage: http://www.med.lu.se/klinvetlund/eeg
5 recent original publications
Kokaia Merab, Holmberg Kristina, Nanobashvili Avtandil, Xu Zhi-Qing D., Kokaia Zaal, Lendahl Urban, Hilke Susanne, Theodorsson Elvar, Kahl Ulrika, Bartfai Tamas, Lindvall Olle, Hökfelt Tomas
Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin
Proceedings of the National Academy of Sciences of the United States of America. 2001; 98: 14006 - 14011
Englund Ulrica, Björklund Anders, Wictorin Klas, Lindvall Olle, Kokaia Merab
Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry.
Proceedings of the National Academy of Sciences of the United States of America. 2002; 99: 17089 - 17094
Jakubs Katherine, Nanobashvili Avtandil, Bonde Sara, Ekdahl Clementson Christine, Kokaia Zaal, Kokaia Merab, Lindvall Olle
Environment Matters: Synaptic Properties of Neurons Born in the Epileptic Adult Brain Develop to Reduce Excitability.
Neuron. 2006; 52: 1047 - 1059
Tønnesen Jan, Toft Sörensen PhD Andreas, Deisseroth Karl, Lundberg Cecilia, Kokaia Merab
Optogenetic control of epileptiform activity.
Proceedings of the National Academy of Sciences of the United States of America. 2009; 106: 12162 - 12167
Woldbye David P D, Ängehagen Mikael, Gøtzsche Casper R, Elbrønd-Bek Heidi, Toft Sörensen PhD Andreas, Christiansen Søren H, Olesen Mikkel V, Nikitidou Litsa, Hansen Thomas V O, Kanter Schlifke Irene, Kokaia Merab
Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures.
Brain : a journal of neurology. 2010; 133: 2778 - 2788
Further publications here (new window)
|Total financing:||4.2 MSEK||Gov grant for clinical research ("ALF"):||0.9 MSEK|
|Total external financing:||3.3 MSEK||Natl and intl prioritized grants:||2.7 MSEK|