Journal of Neuroscience
Vol. 32, Issue 33
15 Aug 2012

journal-of-neuroscience

Cover legend: The hydrophilic domain of rat mitochondrial electron transport chain complex I is involved in the production of cellular ATP. During epileptogenesis, arginine 76 (orange spheres) of the 75 kDa subunit (purple ribbon) is irreversibly modified by carbonylation, leading to decreased complex I activity. This residue is located at the interaction interface between the 75 kDa subunit and the 51 kDa subunit (green ribbons), proximal to the NADH binding site (red sticks) and the sulfur-iron center involved in the initial transfer of electrons into the chain (yellow and purple sticks). For more information, see the article by Ryan et al. (pages 11250–11258​).

Summary: Dr. Patel’s early work addressed a fundamental question in the field of neuroscience; namely, how does excessive glutamate neurotransmission induce excitotoxic cell death? She demonstrated a role for intracellular superoxide radicals in excitotoxic cell death emphasizing the overlapping roles of oxidative stress and excitotoxic injury, two independent pathological mechanisms common to diverse neurological disorders (Patel et al., Neuron 16:345-355, 1996). This discovery led to the overarching theme of her laboratory, which is to understand the role of reactive species and metabolic mechanisms in neuronal disorders such as epilepsy.

Research Areas. The overarching theme of the Patel laboratory is to understand the role of redox processes and metabolic mechanisms in epilepsy, aging and toxicant-induced brain injury. Using biochemical, metabolic, transgenic and translational approaches, research in the laboratory is focused on three major areas: a) understanding the mechanisms of redox and metabolic dysfunction in response to epileptogenic insults, b) developing neuroprotective drugs and therapies and c) identifying metabolic targets of ketogenic diets. The following sections describe the major research areas in the Patel lab.

Defining the role of oxidative stress and metabolic dysfunction in epilepsy and its comorbidities. Epilepsy is a recent addition to the diverse array of acute and chronic neurological disorders in which the role of oxidative stress and mitochondrial dysfunction is rapidly emerging. Our research has been pioneering and instrumental in defining the role of redox and metabolic mechanisms in the pathogenesis of epilepsy and its comorbidities. The laboratory identified subcellular sources of reactive species (RS), their temporal occurrence and functional impact in animal models of temporal lobe epilepsy (TLE). Our focus on mitochondria arose from investigation of subcellular sources of seizure-induced RS, which indicated a disproportionate contribution of mitochondria. Work from our laboratory has demonstrated increased production of mitochondrial reactive oxygen species (mtROS) and persistent depletion of glutathione during epileptogenesis in two animal models. We demonstrated for the first time an oxidative post-translational modification via carbonylation of the 75kDa subunit of CI in experimental TLE. A functional consequence of oxidative damage to mitochondria in epilepsy is a bioenergetics decline, which can increase neuronal excitability. We recently demonstrated that increased ROS indeed result in deficits of mitochondrial respiration in experimental TLE. Finally, we showed that mitochondrial oxidative stress results in mitochondrial dysfunction and neuronal death which contributes to cognitive deficits associated with chronic epilepsy. Our studies suggest redox and mitochondrial pathways as novel therapeutic approaches for modifying acquired epilepsy and associated cognitive deficits. A recent collaboration with Dr. Scott Baraban’s laboratory identified metabolic deficits in genetic models of epilepsy, notably Dravet’s syndrome.

Delineating mitochondrial mechanisms of oxidative brain injury. Mitochondrial oxidative stress is well known to play a pathogenic role in neuronal disorders. However, the mechanisms by which ROS produce damage are incompletely understood. Our research has demonstrated that that superoxide toxicity via oxidative inactivation of mitochondrial aconitase contributes to neuronal death in animal models of neurodegeneration. Studies in the laboratory have identified a novel pool of mitochondrial iron that correlates with mitochondrial aconitase inactivation in brain injury models. We identified mitochondrial complex III as a major source of ROS via redox cycling agents. These studies led to the novel discovery that brain mitochondria consume hydrogen peroxide (H2O2) in a substrate-dependent manner via the thioredoxin/peroxiredoxin pathway linked by mitochondrial nicotinamide transhydrogenase activity. ​​​​

epilepsy-chart

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My overarching research interests focus on how mitochondrial (dys)function can predispose to cognitive deficits associated with aging and neurological disease. Currently, my research project investigates how neuronal-specific deletion of the mitochondrial deacetylase, Sirt3 or its target SOD2, contributes to cognitive dysfunction and/or hyperexcitability and seizures. I also aid in the development of novel therapeutics using rat epileptic models. To address my hypotheses, I use a variety of techniques including cognitive testing, metabolic flux analysis, high resolution respirometry, genomics, acetylomics, EEG and biochemical assays. In addition to developing my expertise as a mitochondrial neurobiologist, I am also a wife and mother. I therefore spend most of my spare time finding my husband’s lost things and convincing my toddler that clothes are indeed a necessary part of life.

jen-pearson-smith

Dr. Jennifer Pearson Smith (Jen)
Senior Post-doctoral researcher

I received my PhD in Cell and Molecular Biology from Lehigh University, where I worked on understanding molecular mechanisms underlying pediatric genetic diseases using zebrafish as a model system. My passion for the zebrafish model system and genetic diseases led me to join the Patel lab to study a genetic form of childhood epilepsy called Dravet syndrome (DS). I am interested in understanding the role of energy metabolism particularly, defects in glucose metabolism as the primary mechanism explaining DS etiology. My ultimate goal is to identify novel metabolic targets for improving disease outcomes in DS. When not in lab I spend most of my free time painting, baking and playing with my two kids.

1) My research focus is on a genetic form of childhood epilepsy called Dravet syndrome (DS). Using both zebrafish and mouse models of Dravet syndrome I hope to identify specific metabolic targets for developing novel therapies to treat DS, and other genetic epilepsies in general.

Rajeswari-Banerji

Dr. Rajeswari Banerji (Raji):
Post-doctoral researcher

My research work focus on: the mechanisms of oxidative damage and the effects of antioxidant therapy in Parkinson’s disease and epilepsy.

Liping-Liang

Dr. Liping Liang
Senior Research Associate

I’m a 5th year Toxicology graduate student. I earned my undergrad and master’s degrees in Biotechnology. I’ve always been fascinated by how certain molecular triggers and mechanisms contribute to disease phenotypes and comorbidities. The goal of my thesis project is to delineate the mechanism(s) by which glutathione redox status modulates neuronal hyperexcitability and seizure behavior. Currently, I’m investigating the role of the mTOR pathway as the mediating link between specific redox changes and seizure activity. As a critical off-shoot of my project, I’m also interested in understanding the complex interconnectivity between neuronal-metabolism (glycolysis, TCA, OXPHOS), oxidative stress and seizures. In my free time (really?! as a graduate student?!), I like to write poems, watch whales and glaciers, hike and drive my friends crazy!!

ashwini-sri-hari

Ashwini Sri Hari
Senior graduate student

Currently, my research involves discovering and characterizing novel phenotypes associated with mice that have neuronal specific Sirt3 and SOD2 gene deletions, especially those phenotypes associated with neuronal hyper-excitability and excitotoxic cell death and changes in metabolic function. Additionally, I am involved in a clinical project focused on examining changes in the microbiome in epilepsy patients before and after receiving the ketogenic diet and how these changes may be associated with diet efficacy.

In my free time, I enjoy reminding my coworkers to complete their health and safety training, taking long walks on the beach, and wondering why my data looks like that.

ruth-fulton

Ruth Fulton
Lab Manager

My main project involves investigating the mechanism that underlies the use of dietary manipulations such as the ketogenic diet to treat epilepsy. In addition to my independent project, I also assist two postdoctoral researchers with their studies using the Seahorse XF Analyzer to study the metabolism of different models of epilepsy. My skill sets have also allowed me to collaborate with different investigators within the university with their metabolic studies. In my free time, I enjoy spending time thinking about how to conquer the world one day.

christopher-quoc-huynh

Christopher Quoc Huynh
Professional Research Assistant

I earned my Bachelor's degrees in Neuroscience and Cellular, Molecular, and Developmental Biology from the University of Colorado in Boulder, where I studied the role of neuroinflammation in drug addiction and chronic pain. I then continued to conduct research at CU Boulder and MD Anderson, as well as at a medical devices company where I developed diagnostic ELISAs. I have now joined the Patel lab as a graduate student in Pharmaceutical Sciences. I plan to investigate the roles of oxidative stress and neuroinflammatory signaling cascades in epileptogenesis. The primary research focus is on the link between seizure-induced neuronal oxidative stress and neuroinflammation and gliosis. Of particular interest is the contribution of these processes to the remodeling of the perineuronal net component of the extracellular matrix. Such alterations within key circuits may lead to the neuronal hyperexcitability characteristic of epilepsy.

I spend my free time skiing off of cliffs, sleeping in the woods on the cold, hard ground, and waking up too early to drag myself up big mountains.

Tim-Fabisiak

Tim Fabisiak
Graduate Student| Pharmaceutical Sciences program

I am currently a second year Neuroscience student, having graduated from the University of Maryland in 2017 with a Bachelor of Science in Psychology. My undergraduate research focused on how children make inductive inferences with limited evidence, and the relationship between spatial development and mathematical ability, with the goal of creating interventions for children with social or mathematical learning deficits. After graduation, I spent two years working as a research technician in the Center for Neuroscience Research at Children’s National Medical Center in Washington DC under the mentorship of Dr. Joseph Scafidi. During this time, my work primarily studied mitochondrial bioenergetics following perinatal hypoxia and white matter alterations and motor deficits in traumatic brain injury. In the Patel Lab, my current interest is in mitochondrial contributions to intercellular signaling, and my current project is interrogating the neuronal contributions to reactive gliosis in epilepsy.

I’ve raced bicycles all through undergrad so when not in the lab I’m often riding my bike, either for fun or for training, or figuring out how much Panda Express is a reasonable amount to eat in one week. You can’t have too much Panda!

Derek-Johnson

Derek Johnson
Graduate Student| Neuroscience Program

NamePhD ProgramCurrent PositionIndustry/
Government/
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Contact
Dr. Derek DrechselToxicologyProject ToxicologistCTEH (Crisis Tested. Expert Solutions)LinkedIn Profile
Dr. Julie MilderToxicologySenior Medical Science Liaison (MSL)Greenwich BiosciencesLinkedIn Profile
Dr. Shane RowleyNeuroscienceLead Scientist, In vivo validationRecursion PharmaceuticalsLinkedIn Profile
Dr. David CantuNeuroscience Associate Director, Medical AffairsSunovion PharmaceuticalsLinkedIn Profile
Dr. Pamela LopertNeuroscience Scientist, Clinical EndpointsmiRagen Therapeutics, IncLinkedIn Profile
Dr. Kristen RyanToxicologyToxicologistNational Toxicology Program/NIEHSLinkedIn Profile
Dr. Jennifer Pearson-SmithNeuroscienceSenior post-doctoral researcherUniversity of Colorado (Anschutz Medical campus)LinkedIn Profile
Dr. Pallavi Bhuyan McElroyToxicologySenior Scientist, Non-clinical safetyThe Janssen Pharmaceutical CompanyLinkedIn Profile
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