Advancing Research into Epilepsy and Other Neurological Disorders
Welcome to the Escayg lab! Our neurogenetics lab uses a combination of human and mouse genetics, molecular techniques, EEG analysis, behavioral analyses, and genome analysis/bioinformatics to study neurological and neuropsychiatric disorders. We are particularly interested in severe forms of childhood epilepsy and mechanistically related disorders such as autism and Alzheimer’s disease. We are actively generating and working on mouse lines with mutations in voltage-gated ion channels, G protein coupled receptors (GPCRs), and ATP6V0C. Current projects in the lab include 1) the identification of human epilepsy genes, 2) the generation and characterization of mouse models of pediatric epilepsy, 3) understanding the mechanisms by which specific mutations lead to epilepsy and associated behavioral abnormalities, and 4) understanding the role of extracellular vesicles (EVs) in seizure development. We are also working towards the development of novel treatments for neurological disorders such as epilepsy, autism and Alzheimer’s disease.
Techniques Used in the Lab
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Generation and analysis of mouse models
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Mouse surgery and EEG analysis
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AAV-modulated gene expression
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Nanoparticle delivery of neuropeptides
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Seizure induction and neuro-inflammation
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Cell-type specific neuromodulation
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Human disease gene discovery
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Mouse behavioral analyses
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Drug development
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Molecular Biology
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Cell culture
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Single-cell expression analyses
Research
Epilepsy. Epilepsy is a neurological disorder that has a major impact on quality of life, and imposes a tremendous burden both on patients and the healthcare system. It affects approximately 1-2% of the general population, making it one of the most common neurological disorders. The word “epilepsy” often conjures up the disturbing image of frightening, violent seizures, and unfortunately a diagnosis of epilepsy is still considered a cause for shame and embarrassment by some. In reality, epilepsy is a highly heterogeneous disorder, with over 40 distinct subtypes classified on the basis of age of onset, clinical features, and electroencephalographic (EEG) profiles. Seizures are the result of brief and transient alterations in neuronal function due to the synchronous and rhythmic firing of large populations of neurons, which in turn can result from a wide variety of insults, such as head trauma, metabolic abnormalities, and genetic factors. Genetic factors are believed to contribute to approximately 70% of all epilepsy cases.
Although several anticonvulsant medications are available, many produce undesirable side effects and almost 1/3 of patients do not achieve adequate seizure control. Consequently, the long-term goal of the research in our lab is to develop more effective epilepsy treatments through a better understanding of genetic defects that cause epilepsy and the mechanisms of seizure generation.
We are particularly interested in treatment resistant (refractory) forms of pediatric epilepsies since these often have a profound impact on the development of the child and impose a tremendous burden on families. One example of a pediatric epilepsy that we are working on is Dravet syndrome (DS) which is caused by loss-of-function mutations in the voltage-gated sodium channel SCN1A. Much of our research is focused on elucidating the mechanisms that underlie childhood epilepsies such as DS, with the long-term objective of using this information to develop improved treatments.
The main areas of research in our lab are briefly described below
Understanding the mechanisms of seizure generation
The overarching goal of our research is to develop more efficacious epilepsy treatments through a better understanding of the mechanisms of seizure generation. Towards this goal, we are generating and characterizing transgenic, knock-in/knock-out, and conditional knockout mouse models of human epilepsy. We freely provide our mice to other investigators. We use a wide variety of specialized techniques in the analysis of our mouse lines, including chemical and electrical methods of seizure induction, behavioral analyses, and long-term video/EEG analysis. We are also exploring the contribution of extracellular vesicles to the development of epilepsy.
Identification of novel disease genes and mutations
The identification of epilepsy genes/mutations continues to be an active area of research in our lab. Through collaborations with clinicians, we identify and sequence patients with epilepsy in order to identified novel disease genes and mutations. We also develop functional analyses to interrogate the pathogenicity of identified genetic variant.
Understanding the cognitive and neuropsychiatric comorbidities in epilepsy
Children with severe forms of epilepsy often display intellectual disability and a range of clinically challenging neuropsychiatric comorbidities. We have expertise with a number of mouse behavioral assays and we are actively using our mouse models to identify and better understand the spectrum of cognitive and behavioral abnormalities that are associated with mutations in specific epilepsy genes.
Others disorders we are working on
In recent years, interesting mechanistic overlaps have emerged between epilepsy and disorders such as autism spectrum disorder, schizophrenia, and Alzheimer’s disease providing us with exciting new research avenues.
Development of novel treatments for refractory epilepsy
The ultimate goal of the research in my lab is to facilitate the development of more efficacious treatments for patients with epilepsy. Since it is unlikely that there will be a ‘silver bullet’ for the treatment of epilepsy, we are taking a multipronged approach in which both established and novel therapeutics are being evaluated using our mouse models. For example, while various neuropeptides are known to provide seizure protection and modify behavior, the clinical use of these compounds for the treatment of epilepsy has been hampered by their poor ability to cross the blood-brain barrier. We are attempting to overcome this obstacle with nanoparticle encapsulation of these neuropeptides.