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TGF-? Signaling as a Novel Therapeutic Target for Mild Traumatic Brain Injury

Award Number: R01NS092868
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: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 03/31/2022

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TGF-? Signaling as a Novel Therapeutic Target for Mild Traumatic Brain Injury - DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of mortality and disability in younger adults worldwide, with an estimated US incidence of 1.5 million per year in the general population. The annual economic costs in the US were estimated at US$76.5 billion. Mild traumatic brain injury (mTBI, also referred to as concussion) accounts for the majority of all TBIs, and a significant portion of mTBI patients suffer from long lasting o even permanent post-concussive syndromes. Repetitive mTBI from multiple concussions is of particular concern for individuals engaged in contact sports or in military operations. Currently no pharmacological therapy is available that augments functional recovery or prevents long-term neuropsychological symptoms associated with TBI. Transforming growth factor-β (TGF-β) is an important injury response factor in the brain and has been implicated in various neurological diseases and in TBI. Using our recently developed mouse model of repetitive mTBI, our preliminary data show that TGF-β is dysregulated after repetitive mTBI and that SRI-011381, a novel small molecule TGF-β agonist developed at Stanford University, when applied 24 h after injury, reduces cognitive deficits and neuroinflammation. Based on these findings, we propose to investigate the long-term changes and the role of TGF-β signaling in repetitive mTBI and to investigate whether activating TGF-β signaling through SRI- 011381 can reduce long-term cognitive deficits and neuropathology associated with repetitive mTBI. In addition to the wide therapeutic time window of SRI-011381, our proposal builds and expands on the results from the extensive preclinical efficacy, pharmacology and toxicology studies in which our lab has been involved. Our ultimate goal is to develop SRI-011381 for clinical testing as a therapeutic for patients with repetitive mTBI. We hope that our clinically relevant experimental design, along with the advantages of SRI-011381 will increase the likelihood of success in clinical testing.


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: 2023 ( Subtotal = -$19,573 )
2023	2020	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/19/2022	NON-COMPETING CONTINUATION	-$19,573
														Subtotal = -$19,573

Issue Date FY: 2020 ( Subtotal = $299,544 )
2020	2020	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/20/2020	NON-COMPETING CONTINUATION	$299,544
														Subtotal = $299,544

Issue Date FY: 2019 ( Subtotal = $299,544 )
2019	2019	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/28/2019	NON-COMPETING CONTINUATION	$299,544
														Subtotal = $299,544

Issue Date FY: 2018 ( Subtotal = $299,544 )
2018	2018	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/24/2018	NON-COMPETING CONTINUATION	$29,956
2018	2018	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/21/2018	NON-COMPETING CONTINUATION	$269,588
														Subtotal = $299,544

Issue Date FY: 2017 ( Subtotal = $300,333 )
2017	2017	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/30/2017	NON-COMPETING CONTINUATION	$30,034
2017	2017	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE BLDG 101 A2-210	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/21/2017	NON-COMPETING CONTINUATION	$270,299
														Subtotal = $300,333

Issue Date FY: 2016 ( Subtotal = $306,651 )
2016	2016	PALO ALTO INSTITUTE FOR RESEARCH & EDUCATION, INC	P.O. BOX V 38	PALO ALTO	CA	94304	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/15/2016	NEW	$306,651
														Subtotal = $306,651

Grand Total All Awards = $1,486,043

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TGF-? Signaling as a Novel Therapeutic Target for Mild Traumatic Brain Injury

Award Number: R01NS092868

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: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 03/31/2022

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