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Identifying compounds that target APOE4 associated brain endothelial dysfunction

Award Number: R61NS124970
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: 02/03/2022
PERIOD OF PERFORMANCE END DATE: 08/20/2023

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Identifying compounds that target APOE4 associated brain endothelial dysfunction - ABSTRACT APOE genotype is a major genetic risk factor for several neurodegenerative disorders. Compared to APOE3, APOE4 is associated with greater cognitive dysfunction in older adults, increases Alzheimer's disease risk and exacerbates progression of vascular dementia, stroke, and traumatic brain injury. Evidence supports a major role of APOE4 in brain endothelial cell (BEC) dysfunction at the blood-brain barrier in all these conditions. BEC dysfunction can lead to neuronal dysfunction through disrupting the complex neuronal homeostatic environment and via entry of proteins and other toxins that can damage neurons directly and via effects on supporting cells. Due to their unique location, BEC are susceptible to signals from the brain and plasma in neurodegenerative disorders, which may be particularly relevant for inflammation. Indeed, APOE4, neuroinflammation, peripheral inflammation and BEC dysfunction are intimately linked to dementia risk/progression. Our novel in vitro data demonstrate that APOE4-BECs have a unique basal phenotype that results in disruption of their barrier function with inflammatory stimuli, which we have also found in vivo. Based on these data our hypothesis is that APOE4-associated BEC dysfunction is a novel therapeutic target for neurodegenerative disorders. Our goals are to develop our in vitro assays (R61 Phase) and conduct screening and target identification (ID) (R33 phase) to identify novel compounds that mitigate inflammation-induced permeability disruption in APOE4-BECs. Our biological rationale is that APOE4 predisposes BECs to inflammation-induced barrier deficits, thereby increasing the risk/progression of adult-onset neurodegenerative disorders. The novelty lies in our isolation protocols and assays to target inflammation- induced increases in paracellular permeability using APOE4-BECs. The clinical relevance is that APOE4 is a risk factor for neurodegenerative disorders for which there are also in vivo models. Therefore, there are pathways for the transition of positive hits targeting APOE4-associated BEC dysfunction from preclinical to clinical studies.


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 = -$2 )
2024	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/14/2024	NEW	-$2
														Subtotal = -$2

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/22/2022	NEW	$0
2023	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/17/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $358,909 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/2/2022	NEW	$358,909
														Subtotal = $358,909

Grand Total All Awards = $358,907

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Identifying compounds that target APOE4 associated brain endothelial dysfunction

Award Number: R61NS124970

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: 02/03/2022

PERIOD OF PERFORMANCE END DATE: 08/20/2023

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