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The role of MAP3K2/3 in modulating neutrophil ROS release and its translational potential

Award Number: R01HL145152
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/24/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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The role of MAP3K2/3 in modulating neutrophil ROS release and its translational potential - Project Summary: The long-term goal of my lab is to understand the signaling mechanisms by which chemoattractants regulate neutrophil functions and their roles in inflammation-related disease models. Chemoattractants stimulate production of reactive oxygen species (ROS) from neutrophils. ROS is chemically reactive and used by neutrophils to eliminate pathogens. It also exerts significant impact on the hosts. Most studies have shown that increases in ROS production are responsible for tissue damage that exacerbates disease conditions including many of the inflammation-related diseases. However, recent evidence, especially human genetic evidence, suggest that ROS's role may be much more complex than previously believed; it also plays a protective role. In the preliminary study of this application, we found that MAP3K2/3 can phosphorylate a key component of NADPH oxidase complex, which is a protein responsible for ROS generation in leukocytes. The elimination of MAP3K2/3 in leukocytes leads to increased generation of ROS and reduced lung damage in two mouse acute lung injury models, which is diminished by inhibiting ROS generation. We thus hypothesize that deactivation of MAP3K2/3 protects the lung against acute injury through a moderate increase in ROS release from leukocytes. In this study we will investigate the signaling mechanisms by which MAP3K2/3 inhibits ROS generation. We will also characterize how MAP3K2/3 inhibition reduces lung damage during acute lung injury and evaluate the therapeutic potential of a MAP3K2/3 inhibitor in mouse acute lung injury models. Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), in which leukocytes play an important role, are common syndromes with a high mortality rate with no effective pharmacological treatments. Thus, our study not only exerts strong impact in understanding of signaling mechanisms for ROS production regulation, but also may have an important clinical implication.


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 = $0 )
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	4	4/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $418,750 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$41,875
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	4	11/30/2021	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $418,750

Issue Date FY: 2021 ( Subtotal = $418,750 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$41,875
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	3	11/23/2020	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $418,750

Issue Date FY: 2020 ( Subtotal = $418,750 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	2	11/26/2019	NON-COMPETING CONTINUATION	$397,812
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	001	2	3/9/2020	NON-COMPETING CONTINUATION	$20,938
														Subtotal = $418,750

Issue Date FY: 2019 ( Subtotal = $418,750 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Lung Diseases Research	000	1	12/20/2018	NEW	$418,750
														Subtotal = $418,750

Grand Total All Awards = $1,675,000

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The role of MAP3K2/3 in modulating neutrophil ROS release and its translational potential

Award Number: R01HL145152

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/24/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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