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The role of beta 2 integrins in macrophage fusion

Award Number: R01HL063199
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1999
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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The role of beta 2 integrins in macrophage fusion - PROJECT SUMMARY Macrophage fusion resulting in the formation of multinucleated giant cells (MGCs) accompanies a variety of disorders associated with chronic inflammation, including the foreign body response (FBR) elicited by implanted biomaterials. MGCs are a major factor contributing to long-term failures in human vascular prosthetic grafts, pacemaker leads, and other implanted medical devices. Despite the long history of research, the molecular and cellular mechanisms of macrophage fusion and, generally, cell-to-cell fusion remain poorly understood. During the current funding period, we have shown that fibrin polymer, but not its precursor, fibrinogen, deposited on the surface of implanted biomaterials, drives macrophage fusion. Our preliminary in vitro studies found that fibrinogen deposited on the surface at its physiological concentration does not support macrophage fusion, consistent with our previous findings that, upon contact with various surfaces, fibrinogen undergoes self-assembly forming nonadhesive soft matrices. Surprisingly, although the three-dimensional (3D) fibrin gel supports adhesion, it does not support fusion. However, removing the gel, leaving a 2D footprint consisting of fibrils attached to the rigid surface, restores macrophage fusion. We hypothesize that adsorbed fibrinogen and deposited fibrin polymer form matrices with different mechanical properties and surface patterns, which macrophages sense, initiating different mechanotransduction responses. Specific Aim 1 is to determine why and how the fibrin polymer drives macrophage fusion during the foreign body reaction to implanted biomaterials. Using cell signaling assays with mechanosensitive molecules, ultrastructural studies, the hydrogels with different stiffness, and micropatterned surfaces, we will examine differential sensing by macrophages of the mechanical properties of 3D and 2D matrices prepared from wild-type and mutant fibrin(ogens) and characterize their architectural features. The knowledge obtained will be translated into generating biomaterials with a reduced ability to support macrophage fusion and testing their properties in vivo bioimplant models. Specific Aim 2 will determine the cellular and molecular organization of the macrophage fusion site. Following our finding that macrophage fusion is initiated by an actin-based protrusion and some preliminary data, we hypothesize that a strong actin-propelled protrusion is formed at the leading edge of a donor macrophage enriched in podosomes and situated within the interface restricted by zipper-forming proteins. Taking advantage of our methodological platform consisting of high-resolution microscopy, live cell imaging, mice with myeloid cell-specific knockouts, and macrophages with knockdowns of selected regulators of branched actin network, we will determine the cellular and molecular determinants of the fusion site and fusion pore formation. Overalls, these studies will define the novel biology of macrophage fusion and characterize new mechanisms that have the potential to modulate the FBR.


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: 2025 ( Subtotal = $512,705 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	001	24	4/25/2025	NON-COMPETING CONTINUATION	$461,436
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	002	24	6/3/2025	NON-COMPETING CONTINUATION	$51,269
2025	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	22	4/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $512,705

Issue Date FY: 2024 ( Subtotal = $512,705 )
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	002	23	6/28/2024	COMPETING CONTINUATION	$51,269
2024	2024	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	001	23	5/3/2024	COMPETING CONTINUATION	$461,436
2024	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	22	4/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $512,705

Issue Date FY: 2023 ( Subtotal = $446,782 )
2023	2023	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	22	1/25/2023	NON-COMPETING CONTINUATION	$446,782
														Subtotal = $446,782

Issue Date FY: 2022 ( Subtotal = $479,666 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	001	21	6/13/2022	NON-COMPETING CONTINUATION	$47,967
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	21	1/1/2022	NON-COMPETING CONTINUATION	$431,699
														Subtotal = $479,666

Issue Date FY: 2021 ( Subtotal = $479,666 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	001	20	5/24/2021	NON-COMPETING CONTINUATION	$47,967
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	20	12/31/2020	NON-COMPETING CONTINUATION	$431,699
														Subtotal = $479,666

Issue Date FY: 2020 ( Subtotal = $479,666 )
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	003	19	9/14/2020	COMPETING CONTINUATION	$226,102
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	001	19	1/7/2020	COMPETING CONTINUATION	$479,666
2020	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	002	18	9/14/2020	NON-COMPETING CONTINUATION	-$226,102
2020	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	18	1/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $479,666

Issue Date FY: 2018 ( Subtotal = $386,250 )
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	18	8/2/2018	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2017 ( Subtotal = $386,250 )
2017	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Blood Diseases and Resources Research	000	17	7/26/2017	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2016 ( Subtotal = $386,250 )
2016	2016	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Cardiovascular Diseases Research	000	16	7/27/2016	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2015 ( Subtotal = $386,250 )
2015	2015	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Cardiovascular Diseases Research	001	15	8/14/2015	COMPETING CONTINUATION	$386,250
2015	2014	ARIZONA STATE UNIVERSITY	PO BOX 876011	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	14	8/13/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $386,250

Issue Date FY: 2014 ( Subtotal = $373,625 )
2014	2014	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	14	11/26/2013	NON-COMPETING CONTINUATION	$343,125
2014	2014	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	001	14	2/26/2014	NON-COMPETING CONTINUATION	$30,500
														Subtotal = $373,625

Issue Date FY: 2013 ( Subtotal = $362,950 )
2013	2013	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	001	13	6/25/2013	NON-COMPETING CONTINUATION	$19,825
2013	2013	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	13	11/20/2012	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $362,950

Issue Date FY: 2012 ( Subtotal = $381,250 )
2012	2012	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	001	12	4/3/2012	NON-COMPETING CONTINUATION	$38,125
2012	2012	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	12	11/18/2011	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $381,250

Issue Date FY: 2011 ( Subtotal = $381,250 )
2011	2011	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	001	11	11/30/2010	COMPETING CONTINUATION	$381,250
2011	2008	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	10	11/30/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $381,250

Issue Date FY: 2008 ( Subtotal = $283,506 )
2008	2008	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	10	6/25/2008	NON-COMPETING CONTINUATION	$283,506
														Subtotal = $283,506

Issue Date FY: 2007 ( Subtotal = $283,506 )
2007	2007	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Blood Diseases and Resources Research	000	9	6/13/2007	NON-COMPETING CONTINUATION	$283,506
														Subtotal = $283,506

Issue Date FY: 2006 ( Subtotal = $298,809 )
2006	2006	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	7	7/12/2006	NON-COMPETING CONTINUATION	$298,809
														Subtotal = $298,809

Issue Date FY: 2005 ( Subtotal = $306,000 )
2005	2005	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Blood Diseases and Resources Research	000	6	6/14/2005	NON-COMPETING CONTINUATION	$306,000
														Subtotal = $306,000

Grand Total All Awards = $8,365,952

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The role of beta 2 integrins in macrophage fusion

Award Number: R01HL063199

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/1999

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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