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Investigation of Mechanosensory Signaling in the Pathogenesis of Traumatic Brain Injury in Human iPSC-derived Cortical Brain Organoids

Award Number: F31NS117075
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/15/2021
PERIOD OF PERFORMANCE END DATE: 04/24/2023

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Investigation of Mechanosensory Signaling in the Pathogenesis of Traumatic Brain Injury in Human iPSC-derived Cortical Brain Organoids - Project Summary/Abstract Global incidence of Traumatic Brain Injury (TBI) is on the rise, particularly among athletes, military personnel, and elderly citizens1. TBI represents a spectrum of mild to severe injuries that share many long-term pathologies and clinical symptoms such as Tau and TDP43 pathology, axonal injury, neuronal death, and increased risk of depression and neurodegenerative diseases2-6. Although end-stage pathologies are well characterized from post-mortem samples, the molecular mechanisms contributing to injury remain poorly understood in part due to the difficulty of studying live brains in human patients and the variable biophysical processes that occur between patients. As a result, available treatment options remain limited and are largely ineffective61. Previous studies of TBI conducted in animal models present with edema, inflammation, and blood-brain barrier disruption following an induced trauma6,7. Although important to the pathophysiology of TBI, this complex cascade of events complicates our ability to accurately understand cell autonomous injury mechanisms. Therefore, a reductionist system to study the response of distinct cell types to TBI would be beneficial for identifying and targeting changes that occur post-injury. To this end, we will utilize a 3-D cortical organoid culture system grown from human induced Pluripotent Stem Cells (iPSCs) to elucidate cell autonomous mechanisms of injury and degeneration caused by TBI8. We have developed a unique system of focused ultrasonic injury to mimic TBI in vitro which recapitulates key pathologic and transcriptional features of in vivo models. This allows for detailed study of both acute and chronic changes following an induced trauma, and provides a platform to integrate environmental and genetic contributions to injury while preserving human-specific biology. Using this system, we will combine bulk RNA-seq transcriptomic analysis with biochemical and immunoassays to uncover novel cell-type specific injury mechanisms. Using iPSC lines from patients with neurodegenerative diseases, we will test how TBI modulates genetically-induced disease mechanisms. Finally, we will test a mouse model of cortical controlled impact (CCI) to validate our findings in vivo. This proposal will greatly enhance our understanding of specific injury mechanisms in discrete cell types and may help to identify novel neuroprotective therapeutic targets.


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 = -$22,073 )
2024	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/22/2024	NON-COMPETING CONTINUATION	-$16,644
2024	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/17/2024	NON-COMPETING CONTINUATION	-$5,429
														Subtotal = -$22,073

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/9/2023	NON-COMPETING CONTINUATION	$942
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/19/2022	NON-COMPETING CONTINUATION	$46,752
														Subtotal = $47,694

Issue Date FY: 2022 ( Subtotal = $46,752 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/10/2022	NON-COMPETING CONTINUATION	$46,036
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/3/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $46,752

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/15/2021	NEW	$45,520
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	1	2/23/2021	NEW	$516
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	2/4/2021	NEW	$0
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	1/27/2021	NEW	$0
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/15/2021	NEW	$0
														Subtotal = $46,036

Grand Total All Awards = $118,409

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Investigation of Mechanosensory Signaling in the Pathogenesis of Traumatic Brain Injury in Human iPSC-derived Cortical Brain Organoids

Award Number: F31NS117075

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/15/2021

PERIOD OF PERFORMANCE END DATE: 04/24/2023

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