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Targeting matrix metalloproteinases to limit immunopathology in airborne infectio

Award Number: R33AI102239
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/18/2012
PERIOD OF PERFORMANCE END DATE: 06/30/2018

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Targeting matrix metalloproteinases to limit immunopathology in airborne infectio - DESCRIPTION (provided by applicant): Airborne pathogens drive lung inflammation and are transmitted from person to person. Furthermore, immune-mediated tissue damage causes morbidity, organ failure and death. Matrix metalloproteinases (MMPs) have a central role in this immunopathology due to their unique ability to degrade the structural components of the lung extracellular matrix. Recently, we have demonstrated that MMPs are critical drivers of tissue damage in human tuberculosis (TB) (Elkington J Clin Invest 2011). Several MMP inhibitors have been developed for other inflammatory conditions and have a proven safety record in man. MMP inhibition may represent a novel adjunctive therapy to shorten the duration of infectivity, and reduce mortality from human airborne respiratory infections. Hypothesis: MMP activity drives matrix destruction, pathogen dissemination and respiratory failure in human airborne infection. Aims: to investigate MMP inhibition as host-targeted therapy for airborne infectious disease by studying two globally important pathogens with contrasting pathologies: (i) Mycobacterium tuberculosis which causes chronic destruction of the lung matrix, and (ii) Influenza which drives rapid matrix remodeling and transmission. We will define the role of MMPs in TB and investigate the therapeutic effects of MMP inhibition to improve patient outcomes by studying in vitro human cellular models and in vivo MMP humanized mice. In vitro models of human TB granulomas will be developed using a bio-electrospray technology to produce 3-dimensional TB-impregnated spheroids to study MMP inhibitors. We will investigate the pathology of mycobacterial infection in MMP-1 humanized mice to define the effects of MMP activity and inhibition in vivo. We will study MMP upregulation by influenza A in epithelial cells monocytes and macrophages. A ferret model of influenza infection will be used to study MMP inhibitory activity in vivo and its ability to reduce immune-mediated tissue damage. Summary: This research identifies MMP inhibitors that limit pathology of airborne infection to reduce morbidity, transmission and mortality. The results are relevant not only to TB and pandemic influenza, but also to other rapidly fatal airborne infections (e.g., SARS coronavirus). We will establish a new therapeutic paradigm targeting excessive host MMP activity to improve outcomes in pulmonary infection.


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: 2019 ( Subtotal = -$58,476 )
2019	2016	UNIVERSITY OF SOUTHAMPTON	UNIVERSITY RD	SOUTHAMPTON	HAMPSHIRE	SO17 1BJ		GBR	Allergy and Infectious Diseases Research	000	5	11/17/2018	NON-COMPETING CONTINUATION	-$58,476
														Subtotal = -$58,476

Issue Date FY: 2016 ( Subtotal = $372,614 )
2016	2016	UNIVERSITY OF SOUTHAMPTON	outhampton University Clinical and	Southampton				GBR	Allergy and Infectious Diseases Research	000	5	7/15/2016	NON-COMPETING CONTINUATION	$372,614
														Subtotal = $372,614

Issue Date FY: 2015 ( Subtotal = $377,585 )
2015	2015	UNIVERSITY OF SOUTHAMPTON	outhampton University Clinical and	Southampton				GBR	Allergy and Infectious Diseases Research	000	4	6/22/2015	NON-COMPETING CONTINUATION	$377,585
														Subtotal = $377,585

Issue Date FY: 2014 ( Subtotal = $392,886 )
2014	2014	UNIVERSITY OF SOUTHAMPTON	outhampton University Clinical and	Southampton				GBR	Allergy and Infectious Diseases Research	000	3	7/18/2014	EXTENSION WITH OR WITHOUT FUNDS	$392,886
														Subtotal = $392,886

Grand Total All Awards = $1,084,609

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Targeting matrix metalloproteinases to limit immunopathology in airborne infectio

Award Number: R33AI102239

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/18/2012

PERIOD OF PERFORMANCE END DATE: 06/30/2018

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