Area:
Neuroscience Biology
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High-probability grants
According to our matching algorithm, Severn B. Churn is the likely recipient of the following grants.
| Years |
Recipients |
Code |
Title / Keywords |
Matching
score |
| 2000 — 2002 |
Churn, Severn Borden |
P50Activity Code Description:
To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
S E Duration Dependent Modulator of Gaba-a Receptor Function @ Virginia Commonwealth University
Status Epilepticus (SE) is a major neurological emergency affecting over 150,000 people/year in the US. Despite advances in treatment strategies, SE is still associated with a significant level of mortality. It has been well- established that a significant number of SE patients respond poorly to treatment. These resistant patients have a much higher mortality rate than patients than respond rapidly to treatment. Therefore, understanding the cellular and molecular mechanisms that result in decreased responsiveness to therapy is essential to develop intervention strategies to better treat this life-threatening condition. SE has been shown to alter GABA/ AR function in a duration-dependent manner. This acute and progressive alteration of GABA/AR function has been attributed to a post-translational modification of the receptor. A significant inhibition of CaM kinase II activity has been observed in multiple animal and in vitro models of SE. In addition, CaM kinase II has been shown to augment GABA/AR function. SE-induced inhibition of CaM kinase II results in decreased GABA/AR sub-unit phosphorylation. This observation has led us to develop the CENTAL HYPOTHESIS that GABAergic inhibition progressively decreases as SE duration increases due in part to alteration in phosphorylation of GABA/AR subunits by CaM kinase II and this may contribute to the induction of BZ resistance and intractability to treatment in prolonged SE. The experimental aims will utilize two well characterized models of SE: The experimental aims will utilize two well characterized models of SE: The rat pilocarpine model (pilo-SE) and the hippocampal neuronal culture model (HNC-SE). Both models of SE show a loss of BZ sensitivity in a duration-dependent manner. Therefore, these models will be utilized to elucidate the cellular and molecular mechanism which result in SE duration-dependent decrease in GABA/AR function, and accomplish the following specific aims: 1) Characterize the effect of SE duration on agonist and allosteric modulator binding and GABA/AR function. 2) Determine the effect of SE duration on CaM kinase II activity and GABA/AR subunit phosphorylation, and 3) Examine whether CaM kinase II-dependent phosphorylation of the GABA/AR alters agonist and allosteric modulator binding and GABA/AR function. Accomplishment of these specific aims will significantly advance our understanding of BZ resistant in SE. Since BZ intervention is the front line therapy for SE patients, understanding the cellular and molecular mechanisms which result in the development of BZ resistance in SE is essential for advancing the clinical management of this neurological emergency. The significance of this research proposal is that it describes a molecular mechanism whereby prolonged seizure activity modulates the function of a major neurotransmitter receptor complex. Understanding the cellular mechanisms that result in altered GABA/AR function in SE is essential to the development of new treatment strategies to manage SE in the clinical setting.
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1 |
| 2002 — 2005 |
Churn, Severn Borden |
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. |
Molecular Mechanisms of Receptor Function in SE @ Virginia Commonwealth University
DESCRIPTION (provided by applicant): Epilepticus (SE) is a major neurological emergency affecting over 150,000 people/year in the US. Despite advances in treatment strategies, SE is still associated with a significant level of mortality. It has been well established that a significant number of SE patients respond poorly to treatment. These resistant patients have a much higher mortality rate than patients that respond rapidly to treatment. Therefore, understanding the cellular and molecular mechanisms that result in decreased responsiveness to therapy is essential to develop intervention strategies to better treat this life-threatening condition. SE has been shown to alter GABAA receptor (GABAAR) function in a duration-dependent manner. This acute and progressive alteration of GABAAR function has been attributed to a post-translational modification of the receptor. A significant inhibition of Calcium/calmodulin-dependent protein kinase II (CaM kinase II) activity has been observed in multiple animal and in vitro models of SE. In addition, CaM kinase II has been shown to augment GABAAR function and SE-induced inhibition of CaM kinase II results in decreased GABAAR subunit phosphorylation. This observation has led us to develop the CENTRAL HYPOTHESIS: GABAA receptor function progressively decreases as SE duration increases due in part to SE-induced inhibition of CaM kinase II dependent positive modulation of GABAAR activity. The experimental aims will utilize two well-characterized models of SE: The rat pilocarpine model and the hippocampal neuronal culture model. Both models of SE show alteration of GABAAR function in a duration-dependent manner. Therefore, these two models will be utilized to elucidate the cellular and molecular mechanisms which result in SE duration-dependent decrease in GABAAR function, and accomplish the following specific aims: 1) Characterize the effect of SE duration on agonist and allosteric modulator binding and GABAAR function. 2) Determine the cellular mechanisms of SE-induced inhibition of GABAAR function. 3) Characterize the CaM kinase II-dependent modulation of GABAAR function. 4) Characterize the molecular mechanisms of CaM kinase Il-dependent phosphorylation on GABAAR function. 5) Determine the effect of direct inhibition of CaM kinase II activity on neuronal physiology and GABAAR function in the absence of SE. Accomplishment of these specific aims will significantly advance our understanding of drug resistance in SE. Since GABAergic intervention is the front line therapy for SE patients, understanding the cellular and molecular mechanisms that result in modulation of GABAAR function in SE is essential for advancing the clinical management of this neurological emergency. The significance of this research proposal is that it describes a molecular mechanism whereby prolonged seizure activity modulates the function of a major neurotransmitter receptor complex. Understanding the cellular mechanisms that result in altered GABAAR function in SE is essential to the development of new treatment strategies to manage SE in the clinical setting.
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1 |