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LEUKOCYTE ADHESION IN ALLERGIC INFLAMMATION

Award Number: R01AI035796
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: 06/01/1995
PERIOD OF PERFORMANCE END DATE: 08/31/2012

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LEUKOCYTE ADHESION IN ALLERGIC INFLAMMATION - DESCRIPTION (provided by applicant): Allergic inflammation is a complex disease that involves the trafficking and mobilization of multiple leukocytes, including eosinophils and T-cells, to sites of inflammation. Increased expression of Th2 cytokines, chemokines, vascular adhesion molecules and growth factors leading to exacerbation of the inflammatory response, including increased airway hyperactivity (AHR), airway remodeling and pulmonary angiogenesis are observed during airway allergic inflammation. Since eosinophils play an important role in the pathogenesis of allergic inflammation, in the last decade we have focused our attention on the mechanisms by which this cell type is generated, how it interacts with the vascular endothelium and how it is recruited to sites of inflammation. These studies have resulted in the identification of key molecules involved in the sequestration of eosinophils to different vascular beds such as the peritoneum and the pulmonary vascular bed. Our preliminary studies suggest that in addition to cell surface selectins and integrins, galectin- 3 (Gal-3), a carbohydrate-binding lectin that recognizes N-glycans expressed by MgatS, can (i) function as a novel vascular and cell adhesion molecule to support eosinophil trafficking, (ii) participate in the generation of Th2 cytokines and (iii) induce AHR in mice. In this competing continuation, we hypothesize that Gal-3 as well as N-glycans expressed by MgatS play an important role in the pathogenesis of acute and chronic airway allergic inflammation including asthma. To examine this, we have proposed three specific aims. In the first aim, using intravital microscopy, we will examine the function of Gal-3 as a novel adhesion molecule that supports cell adhesion by binding to multiple ligands, including N-glycans containing poly N- acetyllactosamine residues, VCAM-1 and alpha4 integrins, to support trafficking of eosinophils under conditions of flow in different vascular beds. In the next aim, using Gal-3-/- and Mgat-5-/- mice, we will determine the role of Gal-3 and Mgat5 in mediating immune responses including, AHR, expression of adhesion molecules and chemokines, Th1/Th2 cytokine release, mast cell activation and survival of inflammatory leukocytes during chronic allergic inflammation. Finally, based on our observation that Gal-3 is expressed in the airways and lung tissue associated with airway remodeling in chronically allergen-challenged mice, we propose to examine the mechanisms by which Gal-3 and its N-glycan-containing ligands expressed by MgatS promote airway remodeling and pulmonary angiogenesis associated with allergic inflammation utilizing Gal-3-/- and Mgat-5-/- mice. Overall, the proposed studies will delineate the importance of Gal-3 and its ligands in acute and chronic phases of airway allergic inflammation. Understanding the role of lectin-carbohydrate interactions in allergic inflammation has the potential to lead to the development of glycan-based therapies (or their mimetics) for the treatment of allergic diseases.


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: 2011 ( Subtotal = $0 )
2011	2009	UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	15	8/19/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $323,629 )
2009	2009	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	15	7/24/2009	NON-COMPETING CONTINUATION	$323,629
														Subtotal = $323,629

Issue Date FY: 2008 ( Subtotal = $323,629 )
2008	2008	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	14	8/5/2008	NON-COMPETING CONTINUATION	$323,629
														Subtotal = $323,629

Issue Date FY: 2007 ( Subtotal = $529,923 )
2007	2007	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	12	8/31/2007	NON-COMPETING CONTINUATION	$529,923
														Subtotal = $529,923

Issue Date FY: 2006 ( Subtotal = $491,175 )
2006	2006	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	11	9/12/2006	COMPETING CONTINUATION	$491,175
														Subtotal = $491,175

Issue Date FY: 2004 ( Subtotal = $414,600 )
2004	2004	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	5/7/2004	NON-COMPETING CONTINUATION	$414,600
														Subtotal = $414,600

Issue Date FY: 2003 ( Subtotal = $414,600 )
2003	2003	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	6/5/2003	NON-COMPETING CONTINUATION	$414,600
														Subtotal = $414,600

Issue Date FY: 2002 ( Subtotal = $352,410 )
2002	2002	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	8/8/2002	NON-COMPETING CONTINUATION	$352,410
														Subtotal = $352,410

Issue Date FY: 2001 ( Subtotal = $439,600 )
2001	2001	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	8/2/2001	NON-COMPETING CONTINUATION	$439,600
														Subtotal = $439,600

Issue Date FY: 2000 ( Subtotal = $439,600 )
2000	2000	LA JOLLA INSTITUTE FOR MOLECULAR MEDICINE	4570 EXECUTIVE DR, SUITE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	9/11/2000	COMPETING CONTINUATION	$439,600
														Subtotal = $439,600

Grand Total All Awards = $3,729,166

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LEUKOCYTE ADHESION IN ALLERGIC INFLAMMATION

Award Number: R01AI035796

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: 06/01/1995

PERIOD OF PERFORMANCE END DATE: 08/31/2012

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