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Translational assessment of sulfonylurea receptor-1 as a biomarker and therapeutic target for cerebral edema in traumatic brain injury

Award Number: K23NS101036
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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PROJECT ABSTRACT There is a fundamental gap in translating preclinical work on complex underlying mechanisms of cerebral edema in traumatic brain injury (TBI) to critically needed biomarkers and targeted/preventive therapies for improving outcomes in humans. This is an important problem because indiscriminate clinical approaches to cerebral edema remain reactionary and morbid - compounding a problem that is a fundamental contributor to death and disability in TBI. The long-term research goal is to better understand the roles and interactions of edema pathways in human TBI. This will focus innovation of successful targeted treatments. The overall objective of this K23 is to develop a comprehensive approach towards understanding a unique, key pathway of cerebral edema in human TBI involving a transmembrane protein: Sulfonylurea Receptor-1 (Sur1). Founded on the central dogma of biology, this proposal evaluates the Sur1-cerebral edema relationship in TBI from multiple angles by investigating Sur1 expression and genetic variability in humans, and complementing this with a clinically relevant, unique, edema-generating mouse-model. The central hypotheses are that 1) Sur1 levels and genetic variability influence cerebral edema and 2) Sur1 expression patterns guide treatment efficacy. The hypotheses have been formulated upon preliminary data generated by the applicant that strongly suggest feasibility. The rationale for the proposal is that complementing Sur1 expression and genetics in human TBI with a relevant animal model, has the potential to directly translate to improving clinical care and outcomes. This is expected to inform patient risk stratification, monitoring, prognosis, and targeting/developing specific therapies. Aim 1 evaluates the relationship between human Sur1 expression (detected in cerebrospinal fluid, CSF, by enzyme linked immunosorbent assay, ELISA), cerebral edema, and TBI outcomes. Aim 2 evaluates the human Sur1 gene (ABCC8) tag-single nucleotide polymorphism (SNP) associations with cerebral edema in TBI. Aim 3 generates a temporo-spatial map of Sur1 expression (by validated techniques) and quantifies effects of Sur1 inhibition by glyburide in an edema-generating mouse-model of TBI. The approach is innovative, in the applicant's opinion, because it molecularly complements generic intracranial pressure (ICP) monitoring and responses to cerebral edema by focusing on a key pathway, and uses a multifaceted approach to bridge the gap between animal models and human disease. These aims are expected to establish the utility of Sur1 as a novel biomarker and evaluate it as a preventive therapeutic target against edema. The proposed work is significant because it has potential groundbreaking implications for monitoring and preventing cerebral edema that may reduce morbidity and mortality, not just in TBI, but in many other neurological disorders. The research plan is augmented by expert mentoring and rigorous didactic training. Together, this will provide the candidate with essential career development in translational research methodologies and the science of biomarkers, modern genetics, and statistics. These synergistic tools cultivate skills necessary for transition to independence. It sets the stage for R01-projects evaluating the interplay between Sur1 expression, genetics and inhibition in clinical trials. This work will uniquely position the investigator as a future leader in the development of individualized targets against cerebral edema to improve outcomes in TBI.


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 = $0 )
2024	2021	DIGNITY HEALTH	185 BERRY ST STE 200	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $188,729 )
2021	2021	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	7/27/2021	NON-COMPETING CONTINUATION	$188,729
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/6/2021	NON-COMPETING CONTINUATION	-$125,157
2021	2020	DIGNITY HEALTH	185 BERRY ST STE 300	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/6/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$125,157
2021	2020	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	9/3/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $188,729

Issue Date FY: 2020 ( Subtotal = $189,624 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/5/2020	NON-COMPETING CONTINUATION	$189,624
														Subtotal = $189,624

Issue Date FY: 2019 ( Subtotal = $188,608 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/16/2019	NON-COMPETING CONTINUATION	$188,608
														Subtotal = $188,608

Issue Date FY: 2018 ( Subtotal = $188,728 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/29/2018	NON-COMPETING CONTINUATION	$188,728
														Subtotal = $188,728

Issue Date FY: 2017 ( Subtotal = $188,608 )
2017	2017	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/6/2017	NEW	$188,608
														Subtotal = $188,608

Grand Total All Awards = $944,297

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Translational assessment of sulfonylurea receptor-1 as a biomarker and therapeutic target for cerebral edema in traumatic brain injury

Award Number: K23NS101036

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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