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Ketogenic protection from ischemic stroke: evaluating the role of blood-brainbarrier integrity

Award Number: R21NS098219
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Despite being a leading cause of death and morbidity in the U.S., ischemic stroke still has limited therapeutic options. In recent years, the protective potential of pre-conditioning has attracted much attention, though given the difficulty in predicting when stroke will occur, its application to preventing stroke in the general population is somewhat limited. However, there are several clinical scenarios where for a period of time, the risk of stroke is dramatically increased, including cardiac/vascular surgery, and recent history of stroke or transient ischemic attack. In these common scenarios, short-term protection conferred by pre-conditioning may offer considerable clinical potential. While the benefit of hypoxic pre-conditioning against stroke has been known for many years, only recently has the neuroprotective effect of a ketogenic diet been demonstrated. While this neuroprotection has largely been attributed to improving metabolic efficiency, thus far, no-one has examined the vascular contribution to this protection. In this R21 application, we hypothesize that a ketogenic diet protects against ischemic stroke by promoting blood-brain barrier (BBB) integrity via increased expression of endothelial tight junction proteins and the vasculo-protective integrin a6ß4. This hypothesis is supported by several observations. First, like mild hypoxia, a ketogenic diet promotes profound angiogenic remodeling in the brain, along with increased expression of key BBB transporter molecules. Second, also like mild hypoxia, a ketogenic diet activates hypoxia-inducible factor (HIF)-1a signaling, suggesting that these two stimuli may achieve neuroprotection via common downstream mechanisms. Third, mild hypoxia upregulates endothelial expression of tight junction proteins, implying that one mode of action of these pre-conditioning stimuli is to promote BBB integrity. Last, we have shown that the endothelial extracellular matrix integrin receptor a6ß4 is upregulated during hypoxic conditioning, and appears to enhance BBB integrity. To test our hypothesis, we propose three specific aims: (1) demonstrate that a ketogenic diet promotes cerebral angiogenesis and increased endothelial expression of vascular remodeling integrins and tight junction proteins, (2) demonstrate that ketogenic-conditioned mice are resistant to ischemic stroke due to enhanced BBB integrity through upregulation of endothelial tight junction proteins and a6ß4 integrin, and (3) define the roles of the angiogenic (a5ß1) and stabilizing (a6ß4) integrins in mediating vascular remodeling in response to a ketogenic diet. These studies will characterize for the first time, the cerebrovascular remodeling events induced by a ketogenic diet and define the contribution of this remodeling to protection from ischemic stroke. We expect to demonstrate that a ketogenic diet promotes robust cerebrovascular remodeling and that ketogenic-conditioned mice will be resistant to ischemic stroke, in part due to enhanced BBB integrity via increased endothelial expression of the vasculo-protective integrin a6ß4 and tight junction proteins. Successful completion of these studies could lead to the development of a novel approach for preventing ischemic stroke in high-risk 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: 2022 ( Subtotal = $11,387 )
2022	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/26/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$11,387
														Subtotal = $11,387

Issue Date FY: 2021 ( Subtotal = -$12,362 )
2021	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/12/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$12,362
														Subtotal = -$12,362

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	4/23/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$9,960
2019	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	4/23/2019	NON-COMPETING CONTINUATION	-$9,960
2019	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/5/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$66,015
2019	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/5/2019	NON-COMPETING CONTINUATION	-$66,015
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $224,375 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/25/2018	NON-COMPETING CONTINUATION	$224,375
														Subtotal = $224,375

Issue Date FY: 2017 ( Subtotal = $296,125 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/18/2017	NEW	$296,125
														Subtotal = $296,125

Grand Total All Awards = $519,525

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Ketogenic protection from ischemic stroke: evaluating the role of blood-brainbarrier integrity

Award Number: R21NS098219

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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