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Influence of Age and Sex on Cerebral Edema Formation Following Traumatic Brain Injury

Award Number: SC3NS127765
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/05/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Influence of Age and Sex on Cerebral Edema Formation Following Traumatic Brain Injury - Traumatic brain injury (TBI) is a serious public health concern. After TBI, elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. A further complication in the treatment of TBI occurs due to lack of clear knowledge on sex differences in TBI. The influence of biological age and sex on the outcomes of TBI is an important but understudied area of research and one of the major reasons for the limited success observed in several TBI-related clinical trials is, attributed to their failure to account for critical sex and age-related differences in disease expression. Considering this gap in knowledge, the major goal of our proposal is to conduct a pre-clinical study that focuses on the influence of age and sex in TBI. One of the most devastating clinical symptoms of TBI is the formation of cerebral edema leading to an increase in intracranial pressure that impairs cerebral perfusion and oxygenation, and contributes to additional ischemic injuries. Maintaining integrity of the blood-brain barrier (BBB), the protective barrier of the brain, and the prevention of the leakage of fluid and proteins from small blood vessels to the extravascular space (microvascular hyperpermeability) are critical to preventing and treating brain vasogenic edema. We propose a novel paradigm of age and sex dependent changes in microvascular hyperpermeability following TBI, and evaluate if an inflammatory-mediated signaling mechanism responsible for this hyperpermeability is age and sex dependent. Our overarching goal is to understand how age and sex of an individual differentially influence vascular permeability and leading to cerebral edema formation following TBI and ultimately develop new and effective therapeutics for head trauma patients of all ages/sex. In this proposal, we will investigate how age and sex differentially control microvascular permeability and molecular pathways that lead to activation of Neutrophil Extracellular Traps (NET) and NLRP3 inflammasome signaling resulting in vascular hyperpermeability, following TBI and how age and sex influence this pathway. Our central hypothesis is that age/sex differentially influence microvascular permeability, cerebral fluid dynamics and outcomes of TBI, in an NET/NLRP3 inflammasome- dependent manner. Increased NET formation that occurs following TBI promotes NLRP3 inflammasome- mediated endothelial tight junction (TJ) breakdown, hyperpermeability and cerebral edema formation in an age and sex dependent manner. Our specific aims are to: 1) Determine the influence of age and sex on microvascular hyperpermeability following TBI; 2) Determine the upstream regulators of microvascular hyperpermeability following TBI and the influence of age and sex. The proposed novel, integrated approach capitalizes on a refined and relevant mouse model of TBI combined with intravital microscopic imaging of microcirculation, thin-section and feeze-fracture electron microscopy of tight junctions, analysis of cerebral fluid dynamics and cellular and molecular biology approaches. Understanding these novel principles will help us find new ways to treat and prevent cerebral edema in head trauma patients in the future, irrespective of their age and sex.


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: 2026 ( Subtotal = $0 )
2026	2025	THE MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $106,500 )
2025	2025	THE MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/18/2025	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2024 ( Subtotal = $103,305 )
2024	2024	THE MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/6/2024	NON-COMPETING CONTINUATION	$103,305
														Subtotal = $103,305

Issue Date FY: 2023 ( Subtotal = $106,500 )
2023	2023	MOREHOUSE SCHOOL OF MEDICINE, INC.	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/11/2023	NON-COMPETING CONTINUATION	$106,500
														Subtotal = $106,500

Issue Date FY: 2022 ( Subtotal = $106,500 )
2022	2022	MOREHOUSE SCHOOL OF MEDICINE, INC., THE	720 WESTVIEW DR SW	ATLANTA	GA	30310	FULTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/3/2022	NEW	$106,500
														Subtotal = $106,500

Grand Total All Awards = $422,805

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Influence of Age and Sex on Cerebral Edema Formation Following Traumatic Brain Injury

Award Number: SC3NS127765

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/05/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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