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Targeting CNTF to increase adult forebrain neurogenesis

Award Number: R01AG029493
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2007
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Targeting CNTF to increase adult forebrain neurogenesis - Project Summary. CNTF mediates the increased SVZ neurogenesis that occurs in the mouse brain after ischemic stroke. We will follow up on our finding that JNK in astrocytes represses CNTF expression and neurogenesis in naïve mice, to test whether systemic treatment with JNK inhibitor can increase neurogenesis after stroke. We will also block the highly related pro-inflammatory ligand IL-6, which we found reduces stroke- induced neurogenesis, with a gp130 inhibitor. Secondly, we have discovered that blood levels of vitronectin (VTN), produced by the liver, only increase in females after stroke, and leaks into the SVZ to induce IL-6 and repress the neurogenic response. We will identify the mechanisms that regulate VTN, focusing on vagal nerve stimulated muscarinic receptors and FAK. Thirdly, we discovered in males that castration caused an unexpected and very robust effect by increasing basal levels of pro-neurogenic CNTF and decreasing detrimental IL-6, and that this was retained after MCAO. We will define the differential signaling pathways underlying this male-specific mechanism and test whether pharmacological blocking of testosterone would increase neurogenesis in males. Aim 1 will determine whether a gp130 inhibitor promotes neurogenesis when given at 6 h or 2 months after a stroke in adult and aged mice, and whether it acts by blocking IL-6. We will also determine whether JNK inhibition would increase neurogenesis after stroke by increasing CNTF, and/or whether JNK inhibitor would further enhance the neurogenic effects of SC144 after MCAO. Aim 2 will define potentially female-specific mechanisms that regulate liver VTN, including FAK and muscarinic acetylcholine receptors, testing pharmacological FAK inhibition and the role of the nervous system innervation of the liver after MCAO. Aim 3 will define the signaling pathways that mediate testosterone’s effects on CNTF, LIF and IL- 6 expression in the SVZ after MCAO, and using intracerebral injection of testosterone after castration, with or without FAK, JNK, ERK or p38 inhibitors, and whether a testosterone blocker can promote neurogenesis after MCAO. These studies will build on our previous work to define novel fundamental intracellular signaling mechanisms that repress and enhance the key cytokines CNTF and IL-6 involved in SVZ neurogenesis following stroke.


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 = $428,670 )
2024	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	15	5/20/2024	NON-COMPETING CONTINUATION	$428,670
														Subtotal = $428,670

Issue Date FY: 2023 ( Subtotal = $428,670 )
2023	2023	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	14	5/4/2023	NON-COMPETING CONTINUATION	$428,670
														Subtotal = $428,670

Issue Date FY: 2022 ( Subtotal = $428,670 )
2022	2022	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	13	5/9/2022	NON-COMPETING CONTINUATION	$428,670
														Subtotal = $428,670

Issue Date FY: 2021 ( Subtotal = $428,670 )
2021	2021	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	002	12	5/17/2021	NON-COMPETING CONTINUATION	$428,670
2021	2020	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	001	11	4/16/2021	COMPETING CONTINUATION	$2,098
2021	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	10	4/16/2021	NON-COMPETING CONTINUATION	-$2,098
														Subtotal = $428,670

Issue Date FY: 2020 ( Subtotal = $428,670 )
2020	2020	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	002	11	8/7/2020	COMPETING CONTINUATION	$428,670
2020	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	001	10	7/29/2020	NON-COMPETING CONTINUATION	$0
2020	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	10	3/11/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $428,670

Issue Date FY: 2018 ( Subtotal = $299,300 )
2018	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	10	4/16/2018	NON-COMPETING CONTINUATION	$299,300
														Subtotal = $299,300

Issue Date FY: 2017 ( Subtotal = $299,300 )
2017	2017	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	9	4/27/2017	NON-COMPETING CONTINUATION	$269,370
2017	2017	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	001	9	6/22/2017	NON-COMPETING CONTINUATION	$29,930
														Subtotal = $299,300

Issue Date FY: 2016 ( Subtotal = $299,300 )
2016	2016	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	8	4/6/2016	NON-COMPETING CONTINUATION	$299,300
														Subtotal = $299,300

Issue Date FY: 2015 ( Subtotal = $290,321 )
2015	2015	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	000	7	4/8/2015	NON-COMPETING CONTINUATION	$290,321
														Subtotal = $290,321

Issue Date FY: 2014 ( Subtotal = $299,300 )
2014	2014	EAST TENNESSEE STATE UNIVERSITY	BOX 24460A	JOHNSON CITY	TN	37614	WASHINGTON	USA	Aging Research	001	6	4/14/2014	COMPETING CONTINUATION	$299,300
2014	2011	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Aging Research	000	5	4/11/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $299,300

Issue Date FY: 2011 ( Subtotal = $282,938 )
2011	2011	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Aging Research	000	5	6/24/2011	NON-COMPETING CONTINUATION	$282,938
														Subtotal = $282,938

Issue Date FY: 2010 ( Subtotal = $294,359 )
2010	2010	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Aging Research	000	4	6/24/2010	NON-COMPETING CONTINUATION	$294,359
														Subtotal = $294,359

Issue Date FY: 2009 ( Subtotal = $297,332 )
2009	2009	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Aging Research	000	3	7/8/2009	NON-COMPETING CONTINUATION	$297,332
														Subtotal = $297,332

Issue Date FY: 2008 ( Subtotal = $297,332 )
2008	2008	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Aging Research	000	2	5/22/2008	NON-COMPETING CONTINUATION	$297,332
														Subtotal = $297,332

Issue Date FY: 2007 ( Subtotal = $303,400 )
2007	2007	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Aging Research	000	1	8/10/2007	NEW	$303,400
														Subtotal = $303,400

Grand Total All Awards = $5,106,232

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Targeting CNTF to increase adult forebrain neurogenesis

Award Number: R01AG029493

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2007

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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