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Mannose binding lectin-dependent complement activation in emphysema

Award Number: K08HL141770
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 12/17/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Mannose binding lectin-dependent complement activation in emphysema - Project summary The mechanisms by which cigarette smoke (CS) activates the complement cascade to cause lung sterile inflammation and COPD progression are not completely understood. Considering the critical role of complement in pathogen-induced inflammation, selective inhibition of the mannose-binding lectin (MBL) complement pathway may result in decreased CS-induced inflammation and emphysema-like airspace enlargement without an indiscriminate inhibition of complement's response to pathogens. In Aim 1 we propose to investigate a novel mechanism of CS-induced lung injury; focusing on whether mannose-binding lectin associated serine protease-2 (MASP-2), the central protease in the MBL pathway, is necessary to induce inflammation and emphysema during CS exposure. In Aim 2 we will investigate whether alpha-1 antitrypsin, a major serine protease inhibitor, binds and inhibits MASP-2. My proposal addresses the clinically relevant question whether selective targeting of complement cascade via MASP-2 inhibition ameliorates lung inflammation and emphysema development in relevant murine models of CS exposure. Our animal studies are complemented by measurements of MASP-2 levels and activity in samples from active smokers with and without COPD. The design and implementation of the proposed coursework and experiments will assist me in gaining expertise in complement biology, enzymology, and perfect my skills in lung stereology. I will train in new techniques, such as miscroscale thermophoresis, isothermal titration calorimetry, and fluorescence resonance energy transfer, FRET - fluorescence lifetime imaging microscopy, FLIM to study alpha-1 antitrypsin binding to MASP-2. These skills and the new research focus on the role of complement system in CS-induced sterile inflammation will allow me to become an independent investigator in a different area of research than my mentor, Dr. Petrache. My committee members and collaborators are strategically positioned to assist me in completing this proposal. National Jewish Health environment, the extraordinary expertise of the mentoring team, and the track record of fruitful collaborations between Dr. Petrache and members of the committee, will ensure a multifaceted and nurturing setting to facilitate my transition to independence. Completion of this project will provide compelling experimental evidences that MASP-2 inhibition using protease inhibitors ameliorates inflammation and lung injury in murine models of emphysema and it can be harnessed as next generation therapeutics in human COPD disease.


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 = -$42,259 )
2024	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	5	4/8/2024	NON-COMPETING CONTINUATION	-$42,259
														Subtotal = -$42,259

Issue Date FY: 2023 ( Subtotal = $158,652 )
2023	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	001	5	6/9/2023	NON-COMPETING CONTINUATION	$0
2023	2023	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	5	12/23/2022	NON-COMPETING CONTINUATION	$158,652
														Subtotal = $158,652

Issue Date FY: 2022 ( Subtotal = $158,652 )
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	4	12/6/2021	NON-COMPETING CONTINUATION	$158,652
														Subtotal = $158,652

Issue Date FY: 2021 ( Subtotal = $158,652 )
2021	2021	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	3	12/1/2020	NON-COMPETING CONTINUATION	$158,652
														Subtotal = $158,652

Issue Date FY: 2020 ( Subtotal = $158,652 )
2020	2020	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	001	2	12/10/2019	NON-COMPETING CONTINUATION	$158,652
2020	2019	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	1	11/27/2019	NEW	$0
														Subtotal = $158,652

Issue Date FY: 2019 ( Subtotal = $158,652 )
2019	2019	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Lung Diseases Research	000	1	12/17/2018	NEW	$158,652
														Subtotal = $158,652

Grand Total All Awards = $751,001

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Mannose binding lectin-dependent complement activation in emphysema

Award Number: K08HL141770

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 12/17/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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