Area:
neuronal differentiation, doublecortin, polarity, epilepsy, circadian rhythms
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High-probability grants
According to our matching algorithm, Judy Shih-Hwa Liu is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2018 |
Liu, Judy Shih-Hwa |
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 Circadian Molecular Clock Is a Biomarker For Epilepsy in Pediatric Focal Cortical Dysplasia
Scientific Abstract: A common heterogeneous non-inherited condition, focal cortical dysplasia (FCD), is the most common cause of refractory focal epilepsy. While FCD is presumably a stable developmental malformation, epilepsy onset is variable and cases of non-epileptogenic FCD are reported. What factors initiate epilepsy in FCD are unknown. Nevertheless, in pediatric epilepsy most therapeutic resections are performed for FCD patients with severely medically refractory seizures. The tissue collected from this procedure allowed us to study epileptogenesis in these cortical malformations. To discover molecular pathways and to identify potential therapeutic targets in epilepsy, we banked resections and performed a transcriptome analysis of the epileptogenic tissue from FCD and a related disorder Tuberous Sclerosis Complex (TSC). Our preliminary transcriptome analysis on surgical samples from intractable focal epilepsy surgical cases included patients with focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). The statistical analysis of gene expression in that study identified a decrease in the mRNA levels of the transcription factor, Circadian Locomotor Output Cycles Kaput (Clock), expression in epileptogenic tissue from both FCD and TSC compared with non-epileptic brain. This result was confirmed by Western analysis in a larger cohort of FCD cases. We found a reduction of Clock in both excitatory and inhibitory neurons. We created mouse lines with selective deletion of Clock in either excitatory neurons in the cortex or inhibitory neurons. We found that mice with specific deletion of the Clock gene in excitatory neurons have spontaneous seizures. Based on these results we hypothesize loss of Clock disrupts downstream gene expression leading to circuit dysfunction and epilepsy. Conversely, maintenance of Clock function prevents circuit and molecular changes causative for epilepsy. We will test this hypothesis in three aims: 1) We will determine the effect of Clock loss of function on cortical microcircuits. 2) We will determine a molecular mechanism for Clock by studying its targets, the PARbZip transcription factors. 3) We will use small molecule modifiers of circadian transcription genetic techniques to rescue the effects of decreased Clock. This approach has the potential to improve epilepsy care by developing new therapeutic strategies and refining epilepsy biomarkers.
|
1.009 |
2019 — 2021 |
Liu, Judy Shih-Hwa |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Circadian Molecular Clock Is a Biomarker For Epilepsy in Focal Cortical Dysplasia
Scientific Abstract: A common heterogeneous non-inherited condition, focal cortical dysplasia (FCD), is the most common cause of refractory focal epilepsy. While FCD is presumably a stable developmental malformation, epilepsy onset is variable and cases of non-epileptogenic FCD are reported. What factors initiate epilepsy in FCD are unknown. Nevertheless, in pediatric epilepsy most therapeutic resections are performed for FCD patients with severely medically refractory seizures. The tissue collected from this procedure allowed us to study epileptogenesis in these cortical malformations. To discover molecular pathways and to identify potential therapeutic targets in epilepsy, we banked resections and performed a transcriptome analysis of the epileptogenic tissue from FCD and a related disorder Tuberous Sclerosis Complex (TSC). Our preliminary transcriptome analysis on surgical samples from intractable focal epilepsy surgical cases included patients with focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). The statistical analysis of gene expression in that study identified a decrease in the mRNA levels of the transcription factor, Circadian Locomotor Output Cycles Kaput (Clock), expression in epileptogenic tissue from both FCD and TSC compared with non-epileptic brain. This result was confirmed by Western analysis in a larger cohort of FCD cases. We found a reduction of Clock in both excitatory and inhibitory neurons. We created mouse lines with selective deletion of Clock in either excitatory neurons in the cortex or inhibitory neurons. We found that mice with specific deletion of the Clock gene in excitatory neurons have spontaneous seizures. Based on these results we hypothesize loss of Clock disrupts downstream gene expression leading to circuit dysfunction and epilepsy. Conversely, maintenance of Clock function prevents circuit and molecular changes causative for epilepsy. We will test this hypothesis in three aims: 1) We will determine the effect of Clock loss of function on cortical microcircuits. 2) We will determine a molecular mechanism for Clock by studying its targets, the PARbZip transcription factors. 3) We will use small molecule modifiers of circadian transcription genetic techniques to rescue the effects of decreased Clock. This approach has the potential to improve epilepsy care by developing new therapeutic strategies and refining epilepsy biomarkers.
|
1.009 |