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RIT1-mediated Protection following Traumatic Brain Injury

Award Number: R01NS102196
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: 02/15/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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RIT1-mediated Protection following Traumatic Brain Injury - Traumatic brain injury (TBI) is a major cause of death and permanent disability in the United States affecting more than 1.7 million individuals each year. TBI not only results in tissue damage and cell death, but can perturb surviving neuronal function, leading to alterations in neural connectivity, abnormal plasticity, and network dysfunction. Due to the inherent diversity in post-TBI dysfunction, a critical need exists for therapeutic interventions that target multiple injury mechanisms. Development of such multi-prong therapeutic approaches could have enormous clinical, social, and economic benefit. However, implementation of this strategy requires the identification of endogenous molecular cascades capable of regulating multiple protective/restorative pathways. The discovery that the Rit GTPase (RIT1) is dramatically down-regulated following cortical contusion injury (CCI) prompted studies to explore the contribution of Rit-directed signaling to functional recovery following TBI. Drawing upon a collection of RIT1 transgenic mice, exciting preliminary data demonstrate that Rit activation reduces in vivo neurodegeneration and alleviates cognitive dysfunction following CCI. Additional data suggest that Rit is critical for post-TBI neurogenesis and promotes synaptic integrity by reducing post-contusion synaptic loss. Collectively these data are the first to demonstrate a significant role for Rit in directing neuroprotection and neuroplasticity following TBI, and suggest that Rit functions as a linchpin regulator of multiple injury response mechanisms following CCI. The overall hypothesis is that: (1) Rit plays a key role in cellular and functional recovery from brain trauma, and (2) that activation of Rit signaling therefore has broad therapeutic potential in the setting of TBI. Three complementary aims guide our studies. Aim 1 will test the hypothesis that contusion-dependent Rit loss disrupts gene expression programs that promote neural survival and neurogenesis. In Aim 2 we will evaluate the extent to which Rit signaling controls neuronal survival after contusive brain injury. The efficacy of Rit-targeted therapies will be evaluated using an inducible knock-in mouse model to permit Rit activation over a clinically relevant period of hours to days after the onset of brain injury. Aim 3 will test the hypothesis that Rit signaling preserves synaptic function following traumatic brain injury using transgenic mice, electrophysiology, and biochemical assays. Overall, these studies are expected to identify Rit as a crucial signal integration hub in the setting of brain injury – orchestrating diverse endogenous pathways that regulate neuronal survival, promote neuronal regeneration, and control neuroplasticity mechanisms.


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: 2025 ( Subtotal = $0 )
2025	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $508,999 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/26/2022	NON-COMPETING CONTINUATION	$458,098
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/28/2022	NON-COMPETING CONTINUATION	$50,901
														Subtotal = $508,999

Issue Date FY: 2021 ( Subtotal = $508,999 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/13/2021	NON-COMPETING CONTINUATION	$508,999
														Subtotal = $508,999

Issue Date FY: 2020 ( Subtotal = $508,999 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/22/2020	NON-COMPETING CONTINUATION	$458,098
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/11/2020	NON-COMPETING CONTINUATION	$50,901
														Subtotal = $508,999

Issue Date FY: 2019 ( Subtotal = $508,999 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/5/2019	NON-COMPETING CONTINUATION	$508,999
														Subtotal = $508,999

Issue Date FY: 2018 ( Subtotal = $508,999 )
2018	2018	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/6/2018	NEW	$508,999
														Subtotal = $508,999

Grand Total All Awards = $2,544,995

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RIT1-mediated Protection following Traumatic Brain Injury

Award Number: R01NS102196

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: 02/15/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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