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Targeting Rho Kinases for Alzheimer's disease Therapeutics

Award Number: R01AG054719
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Targeting Rho Kinases for Alzheimer's disease Therapeutics - Project Summary Current Alzheimer's disease (AD) therapies predominantly focus on amyloid-β (Aβ) peptides, but biomarker studies indicate that Aβ effects may be maximal before onset of clinical symptoms. Downstream of Aβ, synapse loss and intracellular accumulation of the microtubule-associated protein tau correlate strongly with cognitive decline, yet few therapeutic strategies target these mechanisms. Presently, twenty-nine kinase inhibitors are used to treat human diseases, and out of these, two are pan- Rho-associated protein kinases (ROCK) 1 and 2 inhibitors. In the mid-2000s, the ROCKs were identified as putative translational targets to curb Aβ production. However, progress on this exciting avenue languished due to three critical barriers: 1) the lack of connection between ROCKs and AD pathogenesis beyond mechanisms tied to Aβ generation, 2) the lack of genetic models to test the role of ROCK1 or ROCK2 in AD mice, and 3) the lack of kinase inhibitors offering high ROCK-selectivity and brain penetrance. We aim to overcome these barriers with new data linking ROCKs to structural plasticity changes in AD progression and employing new ROCK1 and ROCK2 conditional knockout mice as well as novel pan- and isoform-selective ROCK inhibitors that exhibit high bioavailability and brain penetrance with no gross side-effects. In Aim 1, we will address the contribution of ROCK1 and ROCK2 to Aβ-induced dendritic structure degeneration. In Aim 2, we will test the effects of chronic ROCK inhibition in mouse models of AD, and in Aim 3, we will elucidate the mechanisms by which ROCK1 and ROCK2 mediate tau protein homeostasis and autophagy induction.


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 = -$17,984 )
2024	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	5	1/9/2024	NON-COMPETING CONTINUATION	-$17,984
														Subtotal = -$17,984

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	5	5/13/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2020 ( Subtotal = $371,250 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	4	5/28/2020	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	4/22/2019	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2018 ( Subtotal = $371,250 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	2	6/8/2018	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2017 ( Subtotal = $371,250 )
2017	2017	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	7/5/2017	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,838,266

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Targeting Rho Kinases for Alzheimer's disease Therapeutics

Award Number: R01AG054719

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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