2018 — 2020 |
Maheshwari, Atul |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Cellular and Network Basis of Anti-Epileptic Drug Response @ Baylor College of Medicine
? DESCRIPTION (provided by applicant): Anti-epileptic drug resistance is a major obstacle to the clinical management of seizure disorders and affects one third of patients with epilepsy. In addition, patients with genetic generalized epilepsy do not have the option of epilepsy surgery. The focus of this project is to explore the cellular and network basis of anti-epileptic drug response in genetic generalized epilepsy. The candidate has a strong clinical background in epilepsy and has developed significant preliminary work which forms the basis for the proposed research. The central hypothesis of this proposal is that interictal relative gamma power (30-100 Hz) may predict anti-epileptic drug response in absence epilepsy and severe myoclonic epilepsy of infancy (Dravet Syndrome) due to the effect of these drugs on fast-spiking interneurons. The stargazer and tottering mouse models of epilepsy, as well as the Scn1a heterozygous knock-in model of Dravet Syndrome, are ideal for studying this hypothesis since they have mutations which have been associated with fast-spiking interneuron deficits, and these interneurons are critical for the generation of neocortical gamma rhythms. In addition, these models are known to have paradoxical seizure exacerbation with certain anti-epileptic drugs. In this project, using in vivo 2-photon microscopy and simultaneous EEG, post-hoc immunohistochemistry, and in vivo video-EEG monitoring sampling at 2 kHz, the specific aims of this project are to: (1) Determine the neocortical cell-specific and local network responses to anti-epileptic drugs in vivo in 3 models of genetic generalized epilepsy, and (2) Evaluate the effect of anti-epileptic drugs on interictal EEG power between 2-300 Hz in vivo in the same 3 models of genetic generalized epilepsy. This proposal merges the techniques of computational analysis of EEG previously acquired under the mentorship of Sydney Cash, MD, PhD and more recent techniques acquired under the ongoing mentorship of Jeffrey Noebels, MD, PhD (primary mentor), who provides expertise in neurogenesis, and Stelios Smirnakis, MD, PhD (co-mentor), who provides expertise in 2-photon imaging. In the short term, the candidate has assembled a gap-based plan for rigorous training and coursework focusing on developing expertise in 2-photon imaging and patch-clamp techniques in vivo, statistical modelling and analysis, and translational research methodology, while also learning about and treating patients with epilepsy in a clinical context. In the long term, with a strong institutional commitment and abundant resources available in the Texas Medical Center, this training will aid in the candidate's development as an independent clinician- scientist with a unique focus on diminishing pharmacoresistance in patients with epilepsy. Ultimately, the completion of this research will shed new light on the mechanisms of genetic generalized epilepsy and can directly lead to improved drug development and patient care.
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2021 |
Maheshwari, Atul |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
The Development of Inhibitory Networks Regulating Sustained Attention @ Baylor College of Medicine
Project Summary/Abstract Deficits in sustained attention are common in the general population, and even more common in patients with underlying neuropsychiatric diseases. The diagnosis is complicated by the lack of an objective biomarker, and the most effective treatments are stimulants, which are controlled substances with the potential for abuse or diversion. The focus of this proposal is to explore the use of brain oscillations in the electroencephalogram (EEG) as a translational tool to evaluate the relationship between fast and slow frequencies as an underlying mechanism for attention. This unique EEG signal, known as phase-amplitude coupling (PAC), has the potential to integrate the brain processes involved with focusing attention on a task. The central hypothesis of this proposal is that PAC in the posterior parietal region of the brain in mice coordinates normal attention processes, and this PAC is impaired in mice with attention deficits. Two genetic mouse models of epilepsy have abnormal PAC, one genetic model has the same type of epilepsy but normal PAC, and a fourth genetic model has no epilepsy but abnormal PAC. Testing of these models with simultaneous EEG and behavioral testing, however, has not previously been done. In addition, these models provide mechanistic insight to the disease on a cellular and network level. Using behavioral experiments with simultaneous video-EEG monitoring in mice, the specific aims of this project are to: (1) Demonstrate the relationship between PAC and attention in normal mice; (2) evaluate normal and aberrant PAC throughout development; and (3) determine the relationship between genetic and environmental influences on the development of PAC and sustained attention. This proposal uniquely approaches these aims by merging computational analysis of EEG, behavioral studies, and pharmacological/genetic manipulations over the course of neurodevelopment. In the short term, the work from this proposal will elucidate the developmental mechanisms underlying sustained attention on a network level. In the long term, this work may validate the use of PAC as a translational biomarker for drug discovery in rodents as well as aid in the diagnosis, prognosis, and treatment of patients with deficits in attention. Ultimately, the completion of this research will shed new light on the relationship between brain oscillations, behavior and therapy, and can directly lead to improvements in drug development, neurofeedback, and patient care.
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