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MOLECULAR MECHANISMS OF IL-4 AND IL-13 SIGNALING

Award Number: R01AI038985
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: 05/01/1996
PERIOD OF PERFORMANCE END DATE: 06/30/2011

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MOLECULAR MECHANISMS OF IL-4 AND IL-13 SIGNALING - DESCRIPTION (provided by applicant): The cytokines IL-4 and IL-13 are produced by Type 2 (TH2) helper T cells in response to antigen receptor engagement, by mast cells and basophils upon cross-linkage of the high affinity receptor for immunoglobulin E (IgE), and by activated eosinophils. These two cytokines elicit similar responses in vitro, many of which are associated with allergy and asthma. These responses are elicited by binding to two types of high affinity receptor complexes (Type I and Type II) and initiating signal transduction pathways primarily dictated by the IL-4Ra chain. The regulation of TH2 development and mucus secretion by lung epithelial cells are key responses shown to be regulated by the IL-4Ra during allergic inflammation and are dependent upon STAT6 expression. In addition, we recently found that expression of the IL-4Ra on bone-marrow derived, non-lymphoid cells greatly enhances the eosinophilic inflammation in the lungs in an ovalbumin induced model of allergic inflammation. Preliminary phenotyping suggests a role for signaling by the IL-4Ra on MHC Class II+, CD11b+ mononuclear cells and on eosinophils. It is not known if these cells are primarily responding to IL-4 or IL-13. We have found a differential ability of IL-4 and IL-13 to induce the IRS2 signaling pathway that is recruited by a sequence motif in the IL-4Ra called the I4R-motif. Our broad goal of this application is to understand the molecular mechanisms of signaling through the IL-4Ra by IL-4 and IL-13 and its contribution to the pathogenesis of asthma. Based on our preliminary results, we propose that signaling by the Type I receptor preferentially activates the IRS2 signaling pathway, that signaling by the IL-4Ra expressed on macrophages and/or eosinophils substantially contributes to the severity of allergic inflammation, and that the critical signaling is mediated by IL-4 through the Type I receptor, rather than by IL-13. The specific aims designed to test these hypotheses are 1) To characterize the differences in signaling responses between IL-4 and IL-13, 2) To elucidate differences in IL-4- and IL-13- induced biological responses in macrophages and eosinophils, and 3) To test the contribution of the IL-4Ra+ macrophages and eosinophils to the severity of allergic lung inflammation in vivo. Therapeutic strategies targeting the cytokines IL-4 and IL-13 or their receptors and signaling pathways are currently being developed to treat allergy and asthma. Our studies will provide a greater understanding of their mechanism of action and contribution to allergic inflammation. This new knowledge could help to develop better approaches to treat allergy and asthma.


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: 2010 ( Subtotal = $357,117 )
2010	2010	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	16	5/26/2010	NON-COMPETING CONTINUATION	$350,099
2010	2010	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Trans-NIH Recovery Act Research Support	001	16	7/26/2010	SUPPLEMENT FOR EXPANSION	$7,018
														Subtotal = $357,117

Issue Date FY: 2009 ( Subtotal = $353,635 )
2009	2009	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	15	6/30/2009	NON-COMPETING CONTINUATION	$353,635
														Subtotal = $353,635

Issue Date FY: 2008 ( Subtotal = $353,635 )
2008	2008	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	14	6/11/2008	NON-COMPETING CONTINUATION	$353,635
														Subtotal = $353,635

Issue Date FY: 2007 ( Subtotal = $360,484 )
2007	2007	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	13	7/3/2007	NON-COMPETING CONTINUATION	$360,484
														Subtotal = $360,484

Issue Date FY: 2006 ( Subtotal = $371,250 )
2006	2006	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	12	6/16/2006	COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2005 ( Subtotal = $438,157 )
2005	2005	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	737 WEST LOMBARD STREET	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	11	4/8/2005	NON-COMPETING CONTINUATION	$438,157
														Subtotal = $438,157

Issue Date FY: 2004 ( Subtotal = $422,704 )
2004	2004	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	737 WEST LOMBARD STREET	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	10	8/30/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$371,663
2004	2004	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Allergy and Infectious Diseases Research	000	9	3/19/2004	NON-COMPETING CONTINUATION	$51,041
														Subtotal = $422,704

Issue Date FY: 2003 ( Subtotal = $346,950 )
2003	2003	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Allergy and Infectious Diseases Research	000	8		NON-COMPETING CONTINUATION	$346,950
														Subtotal = $346,950

Issue Date FY: 2002 ( Subtotal = $346,950 )
2002	2002	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Allergy and Infectious Diseases Research	000	7	6/7/2002	NON-COMPETING CONTINUATION	$346,950
														Subtotal = $346,950

Issue Date FY: 2001 ( Subtotal = $346,950 )
2001	2001	AMERICAN NATIONAL RED CROSS HEADQUARTERS	600 A FOREST POINT CIRCLE	CHARLOTTE	NC	28273	MECKLENBURG	USA	Allergy and Infectious Diseases Research	000	6	1/18/2001	COMPETING CONTINUATION	$346,950
														Subtotal = $346,950

Grand Total All Awards = $3,697,832

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MOLECULAR MECHANISMS OF IL-4 AND IL-13 SIGNALING

Award Number: R01AI038985

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: 05/01/1996

PERIOD OF PERFORMANCE END DATE: 06/30/2011

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