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Progressive seizure-induced cardiorespiratory dysfunction in a novel mutant rat model of seizure disorder

Award Number: R01HL122358
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary More than 50 million people suffer from epilepsy globally. Current anti-epileptic drugs (AEDs) cannot prevent seizures in ~30% of these patients, leading to uncontrolled or refractory epilepsy. Unfortunately, these patients are at extreme risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is the leading cause of death in this cohort. Based on landmark SUDEP studies, the current hypothesis is that recurrent seizures induce extreme cardiorespiratory suppression and/or failure through negative effects on the neural networks that regulate vital functions such as breathing, heart rate and blood pressure. However, it remains unclear how repeated seizures fundamentally affect cardiorespiratory control networks within the brainstem, and by what mechanisms these vital systems fail in SUDEP. Here we aim to characterize the pathophysiologic consequences of repeated seizures in a novel rat model with a known mutation in a potassium channel gene (kcnj16; SSkcnj16-/- rats), in which a specific sound of mild intensity readily and reproducibly causes generalized tonic-clonic seizures (GTCSs). Sound-induced GTCSs in SSkcnj16-/- rats led to a stereotypic pattern of events similar to that described in epilepsy patients, including post-ictal generalized EEG suppression and apnea, followed by respiratory rate (RR) and heart rate (HR) suppression. Repeated seizures (1/day for up to 10 days) led to: 1) augmented post- ictal suppression of RR and HR, reduced ventilatory responses to hypoxic and hypercapnic challenges, and unexpected mortality in ~33% of these rats. Brainstem tissue analyses of SSkcnj16-/- rats exposed to repeated seizures showed evidence of time-dependent increases in inflammation and dysregulation of adenosine (ADO) and serotonin (5-HT) – two powerful modulators of cardiorespiratory neural networks. Finally, pharmacologically augmenting 5-HT with an SSRI (fluoxetine) prevented the progressive suppression of post-ictal RR with repeated seizures. Herein we will test our central hypothesis that repeated seizures cause a progressive brainstem pathology initiated by neuroinflammation and mediated by ADO and 5-HT dysfunction leading to cardiorespiratory suppression and/or failure in SUDEP. The proposed studies utilizing this novel mutant rat model will provide: 1) a comprehensive characterization of the progressive pathophysiological responses to repeated audiogenic seizures, and sequence of events leading to unexpected death (Aim 1), 2) identified mechanisms of dysfunction in inflammatory and/or neuromodulatory pathways within critical cardiorespiratory brainstem nuclei negatively affected by repeated seizures (Aim 2), and 3) interventions that functionally test our hypothesis by blocking neuroinflammation or modulating ADO or 5-HT system activity on the backdrop of repeated seizures (Aim 3). We will utilize a combination of established and cutting-edge technologies to provide unprecedented molecular, cellular and systems-level insights into the pathophysiological consequences repeated seizures on vital control systems in order to identify novel targets for therapeutic interventions aimed at preventing or mitigating the risk of SUDEP in human epilepsy patients.


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: 2024 ( Subtotal = $522,541 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	9	3/22/2024	NON-COMPETING CONTINUATION	$522,541
														Subtotal = $522,541

Issue Date FY: 2023 ( Subtotal = $580,601 )
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	8	5/23/2023	NON-COMPETING CONTINUATION	$580,601
2023	2023	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	001	8	6/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $580,601

Issue Date FY: 2022 ( Subtotal = $580,601 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	7	5/27/2022	NON-COMPETING CONTINUATION	$580,601
														Subtotal = $580,601

Issue Date FY: 2021 ( Subtotal = $670,432 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	001	6	6/23/2021	COMPETING CONTINUATION	$67,043
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	003	6	8/10/2021	COMPETING CONTINUATION	$23,415
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	6	4/22/2021	COMPETING CONTINUATION	$603,389
2021	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	002	5	8/10/2021	NON-COMPETING CONTINUATION	-$23,415
														Subtotal = $670,432

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	001	5	8/15/2019	NON-COMPETING CONTINUATION	$2,500
2019	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	5	4/30/2019	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $385,000 )
2018	2018	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	4	4/29/2018	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2017 ( Subtotal = $385,000 )
2017	2017	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	3	3/31/2017	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2016 ( Subtotal = $384,375 )
2016	2016	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	2	3/10/2016	NON-COMPETING CONTINUATION	$385,000
2016	2016	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	001	2	4/18/2016	NON-COMPETING CONTINUATION	-$625
														Subtotal = $384,375

Issue Date FY: 2015 ( Subtotal = $382,500 )
2015	2015	MEDICAL COLLEGE OF WISCONSIN, INC	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Lung Diseases Research	000	1	4/17/2015	NEW	$382,500
														Subtotal = $382,500

Grand Total All Awards = $4,276,050

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Progressive seizure-induced cardiorespiratory dysfunction in a novel mutant rat model of seizure disorder

Award Number: R01HL122358

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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