This proposal provides a mentored career development plan and research proposal designed to facilitate the principal investigator's transition to an independent clinician-researcher. Epilepsy affects ~1.7% of the US population at some point during life and ~33% of patients have seizures that are not controlled by medication. Options for this group are limited but one treatment from antiquity, the ketogenic diet, was shown in a recent randomized trial to induce a 75% decrease in seizures in children (vs those waiting to start the diet) over three months. However, the mechanisms of the diet's anticonvulsant actions are not understood. The ketogenic diet induces major changes in metabolism. The mTOR pathway integrates multiple metabolic signals and its inhibition leads to many changes, including degradation of cellular components including mitochondria. Mitochondrial degradation also affects key neuronal processes that govern mitochondrial localization and function. Mitochondria have multiple functions in neurons, such as maintaining neuronal energy status for the maintenance of electrochemical gradients and release of neurotransmitters. Synaptic localization of mitochondria is critical for normal synapse morphology and firing. Our hypothesis is that nutrient-sensing pathways induced by the ketogenic diet lead to changes in mitochondrial dynamics and localization in specific neuron subsets. Three goals are proposed: (1) determine the role of a nutrient-sensing pathway in metabolism- based anticonvulsant therapy;(2) determine the cell-type specificity of the effects of the ketogenic diet;and (3) determine the effects of the ketogenic diet on mitochondrial dynamics, and the dependence of these effects on mTOR. These studies are expected to identify new targets for the treatment of epilepsy and unravel the mechanisms of metabolism-based therapy. This information will be valuable for the development of clinical treatments that are more effective and more convenient to implement than dietary modification. An individualized career development plan is outlined in detail. This proposal will be carried out under the mentorship of Dr. J. Marie Hardwick, David Bodian Professor at Johns Hopkins Schools of Public Health and Medicine, an expert in mitochondrial dynamics and the factors that regulate these processes. The plan utilizes the expertise of experienced collaborators and includes specific plans for relevant training. Johns Hopkins is an internationally-recognized center for Pediatric Epilepsy and is one the few institutions where different types of metabolism-based therapy in epilepsy have been implemented continuously for over 70 years. The principal investigator's long-term goal is to make significant contributions towards identifying novel targets in the treatment of medically intractable epilepsy in children.
Over one-third of patients with epilepsy do not respond to the available drugs. One option for these patients is the ketogenic diet, which significantly decreases seizures in one half of patients who use it. However, essentially nothing is known about the anticonvulsant mechanisms involved. This proposal pursues a potential underlying mechanism of the ketogenic diet in epilepsy and is expected to identify a specific molecular target that will guide future development of new therapeutic strategies.
|Dolce, Alison; Santos, Polan; Chen, Weiran et al. (2018) Different ketogenesis strategies lead to disparate seizure outcomes. Epilepsy Res 143:90-97|
|Holden, Kylie; Hartman, Adam L (2018) d-Leucine: Evaluation in an epilepsy model. Epilepsy Behav 78:202-209|
|Metz, Kyle A; Teng, Xinchen; Coppens, Isabelle et al. (2018) KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. Ann Neurol 84:766-780|
|Weatherly, Choyce A; Du, Siqi; Parpia, Curran et al. (2017) d-Amino Acid Levels in Perfused Mouse Brain Tissue and Blood: A Comparative Study. ACS Chem Neurosci 8:1251-1261|
|Hartman, Adam L; Santos, Polan; O'Riordan, Kenneth J et al. (2015) Potent anti-seizure effects of D-leucine. Neurobiol Dis 82:46-53|
|Danial, Nika N; Hartman, Adam L; Stafstrom, Carl E et al. (2013) How does the ketogenic diet work? Four potential mechanisms. J Child Neurol 28:1027-33|
|Hartman, Adam L; Rubenstein, James E; Kossoff, Eric H (2013) Intermittent fasting: a ""new"" historical strategy for controlling seizures? Epilepsy Res 104:275-9|
|McNally, Melanie A; Soane, Lucian; Roelofs, Brian A et al. (2013) The N-terminal helix of Bcl-xL targets mitochondria. Mitochondrion 13:119-24|
|Hartman, Adam L; Stafstrom, Carl E (2013) Harnessing the power of metabolism for seizure prevention: focus on dietary treatments. Epilepsy Behav 26:266-72|
|McNally, Melanie A; Hartman, Adam L (2012) Ketone bodies in epilepsy. J Neurochem 121:28-35|
Showing the most recent 10 out of 12 publications