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Mechanisms regulating KCC2 hypofunction during refractory seizures in a mouse model of ischemic neonatal seizures

Award Number: R01HD090884
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project summary/abstract: The long-term goal of this research project is to gain an understanding of the broader relationship between phenobarbital-resistant seizures in neonates, the role of KCC2 hypofunction in the emergence of refractory seizures, and the efficacy of novel KCC2 functional enhancers in a mouse model of neonatal ischemic seizures. Refractory neonatal seizures are highly correlated with childhood seizure syndromes and cognitive disabilities. The development of more effective therapies will benefit from a deeper understanding of the pathophysiology and mechanisms of underlying refractoriness and epileptogenesis in animal models. The KCC2 chloride co-transporter is the chief Cl- extruder in central nervous system neurons. Severe impairment in a neurons ability to extrude Cl- reverses the transmembrane Cl- gradient resulting in GABA mediated depolarization instead of hyperpolarization. Excitotoxic insults in neonatal brains are often associated with severe seizure burdens that are commonly refractory to first-line therapeutic interventions with GABA agonists like phenobarbital. Our previous work has shown that ischemia significantly downregulates Cl- co-transporter KCC2 expression but NKCC1 expression which is the Cl- importer remains unaffected with trends of upregulation in post-ischemic brains. Rescuing the pathophysiological hypofunction of KCC2 following ischemic insults is an untested strategy in neonatal brains. Hypothesis: Rescuing KCC2 hypofunction in neonatal ischemia will restore the physiological levels of synaptic inhibition and neuronal network activity. This rescue will prevent the emergence of refractory seizures and successfully reduce seizure burdens with GABA agonists which in turn will be disease modifying in the long-term. Aims: 1.Plot the dynamics of early and acute KCC2 degradation following ischemia and investigate the regulation of intrinsic KCC2 hypofunction during ischemic seizures. 2. Document the KCC2 degradation related depolarization of cortical neurons following ischemia and the effects of a KCC2 agonist on such depolarization in-vitro 3. Rescue refractory ischemic - seizures in-vivo with a novel KCC2 agonist and quantitate effect on long-term co-morbidities. Deliverables: Upon successful completion of this project, we will move closer to understanding the link between the dynamic changes of KCC2 expression during neonatal seizures to the emergence of refractoriness. Impact and Innovation: Understanding the mechanisms by which the immature brain is transformed with repeated seizures in the neonatal period will help guide evidence-based strategies into treatments for intractable seizures that are often associated with severe long-term co-morbidities in children.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	5	6/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	5	5/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $327,986 )
2021	2021	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	5	6/29/2021	NON-COMPETING CONTINUATION	$327,986
														Subtotal = $327,986

Issue Date FY: 2020 ( Subtotal = $355,470 )
2020	2020	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	4	6/29/2020	NON-COMPETING CONTINUATION	$355,470
														Subtotal = $355,470

Issue Date FY: 2019 ( Subtotal = $410,541 )
2019	2019	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	3	6/18/2019	NON-COMPETING CONTINUATION	$410,541
														Subtotal = $410,541

Issue Date FY: 2018 ( Subtotal = $425,271 )
2018	2018	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	6/21/2018	NON-COMPETING CONTINUATION	$425,271
														Subtotal = $425,271

Issue Date FY: 2017 ( Subtotal = $389,925 )
2017	2017	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	6/29/2017	NEW	$389,925
														Subtotal = $389,925

Grand Total All Awards = $1,909,193

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Mechanisms regulating KCC2 hypofunction during refractory seizures in a mouse model of ischemic neonatal seizures

Award Number: R01HD090884

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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