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The Roles of LPS-Binding Protein Vascular Peroxidase-1 in Innate Immunity

Award Number: R01AI141724
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: 01/04/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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The Roles of LPS-Binding Protein Vascular Peroxidase-1 in Innate Immunity - PROJECT SUMMARY Pneumonia is a leading cause of mortality worldwide, affecting approximately 450 million people globally per year, and results in about 4 million deaths annually. Although the need for research directed toward development of new antibiotics is urgent, the need to study and better understand host immune responses has never been greater. Our previous studies identified and characterized a new member of animal heme-containing peroxidase (hPx) family, Vascular peroxidase 1 (VPO1). Like other members of the hPx family, VPO1 generates hypohalous acids and is able to kill bacteria. Our data show that VPO1-deficient mice have decreased survival in pneumonia. In addition to its catalytic domains, VPO1 has a unique N-terminus containing five leucine-rich repeats and four immunoglobulin domains, which bind with high specificity to lipopolysaccharide (LPS), and kill gram-negative bacteria. Furthermore, our data reveal that LPS causes stronger inflammatory responses in VPO1-deficient mice; VPO1 can inhibit LPS-mediated activation of Toll-like receptor 4. These results lead to our central hypothesis that VPO1 has a bifunctional role in innate immunity, both via bactericidal activities and inhibition of LPS-mediated inflammatory responses. Guided by strong preliminary data, we propose to pursue three Specific Aims: (1) define the molecular mechanisms of VPO1-mediated bactericidal activities; (2) evaluate functional roles of VPO1 in regulation of LPS-mediated inflammatory responses; (3) assess whether exogenous delivery of VPO1 restores host defense function in VPO1-deficient mice. Collectively, our proposed research will broadly impact the field by determining and characterizing a new host defense enzyme, VPO1, with dual function in bacterial killing and reduction of LPS-stimulated inflammation. These studies will uncover new molecular mechanisms of host-pathogen interaction and potentially provide a novel (beyond antibiotics) therapeutic strategy of immune-modulation to treat pneumonia and endotoxin septic shock.


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	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	8/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $371,250 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	4	12/13/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2021 ( Subtotal = $371,250 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	3	12/21/2020	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	Allergy and Infectious Diseases Research	000	2	2/7/2020	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	Allergy and Infectious Diseases Research	000	1	1/3/2019	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,485,000

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The Roles of LPS-Binding Protein Vascular Peroxidase-1 in Innate Immunity

Award Number: R01AI141724

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: 01/04/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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