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LRRK2 Kinase Activity and Mitochondrial Oxidative Stress

Award Number: R21NS106319
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: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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LRRK2 Kinase Activity and Mitochondrial Oxidative Stress - PROJECT SUMMARY/ABSTRACT Leucine-Rich Repeat Kinase 2 (LRRK2) is a potential therapeutic target for Parkinson’s disease (PD) intervention. Mutations in LRRK2 are currently the most common genetic causes of PD, and several of these mutations directly or indirectly increase LRRK2 kinase activity. Furthermore, LRRK2 kinase activity has been implicated in its toxicity to neurons, and LRRK2 mutations may be pathogenic in other cell types such as microglia and those in peripheral tissues, causing symptoms associated with inflammation and gastrointestinal distress. The recent identification of endogenous LRRK2 kinase substrates as well as biochemical and genetic studies suggest that LRRK2 mutations cause dysfunction in a host of processes including autophagy, cytoskeletal dynamics, mitochondrial function, and synaptic transmission; however, the precise mechanisms by which LRRK2 mutants cause pathology are not understood. Elevation of oxidative stress is a major cellular mechanism of pathogenesis that has been associated with LRRK2, and recent evidence suggests that PD-associated mutations in LRRK2 increase levels of reactive oxygen species originating from damaged mitochondria. However, there are currently no tools to directly measure LRRK2 kinase activity in real-time in live cells in correlation with oxidative stress. Thus, in this project we will develop genetically-encoded fluorescent protein based sensors to overcome this technological barrier. Furthermore, these sensors will provide a key technology to directly analyze LRRK2 kinase activity in live cells, tissues, and animals, and they will be particularly well- suited for longitudinal experiments with respect to aging or drug treatments. The primary outcome of this project will be sensor technologies that are optimized for use by the research communities studying Parkinson’s disease, LRRK2, and oxidative stress.


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 = -$71,039 )
2023	2019	WELLESLEY COLLEGE	106 CENTRAL ST	WELLESLEY HILLS	MA	02481	NORFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/29/2023	NON-COMPETING CONTINUATION	-$71,039
														Subtotal = -$71,039

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	WELLESLEY COLLEGE	106 CENTRAL ST	WELLESLEY	MA	02481	NORFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	WELLESLEY COLLEGE	106 CENTRAL ST	WELLESLEY	MA	02481	NORFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,041
2020	2018	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/5/2020	NEW	-$2,041
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $182,176 )
2019	2019	WELLESLEY COLLEGE	106 CENTRAL ST	WELLESLEY	MA	02481	NORFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/13/2019	NON-COMPETING CONTINUATION	$182,176
2019	2018	WELLESLEY COLLEGE	106 CENTRAL ST	WELLESLEY	MA	02481	NORFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$65,000
2019	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/11/2019	NEW	-$65,000
														Subtotal = $182,176

Issue Date FY: 2018 ( Subtotal = $192,785 )
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/7/2018	NEW	$192,785
														Subtotal = $192,785

Grand Total All Awards = $303,922

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LRRK2 Kinase Activity and Mitochondrial Oxidative Stress

Award Number: R21NS106319

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: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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