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Molecular Recognition Studies of the Interleukin-7 Pathway

Award Number: R01AI072142
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: 01/15/2008
PERIOD OF PERFORMANCE END DATE: 12/31/2012

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Molecular Recognition Studies of the Interleukin-7 Pathway - DESCRIPTION (provided by applicant): Interleukin-7 (IL-7) is an essential pleiotrophic cytokine regulating numerous immunological events. Normal IL-7 signaling responses trigger the development, proliferation, and homeostasis of T and B cells as well as remodeling of the extracellular matrix. IL-7 activates its signaling cascade by interacting with its own cell surface receptor, IL-7R alpha, and the common gamma chain receptor through a cytokine-induced receptor heterodimerization mechanism. Under- and over-stimulation of the IL-7 pathway has been implicated in the pathogenesis of a form of severe combined immunodeficiency, autoimmune conditions, coronary artery disease, and several cancers. Structural, energetic, and cell biological studies of IL-7-induced receptor heterodimerization require a careful analysis of two distinct events: the association of IL-7 to IL-7R alpha and of IL-7:IL-7R alpha complex to the common gamma chain receptor. This research proposal will focus on the initiation step, the binding interaction of IL-7 with its alpha receptor. Results show that glycosylation of the IL- 7R alpha confers optimal binding affinity to IL-7. The importance of glycosylation of the IL-7R alpha appears to be a novel binding recognition mechanism for the common gamma chain receptor family. The thermodynamic and kinetic properties of the wild-type IL-7:IL-7R alpha interaction will be ascertained using a variety of biophysical methods including isothermal titration calorimetry and surface plasmon resonance. The functional epitopes on both IL-7 and IL-7R alpha will be determined using site-directed scanning mutagenesis, biophysical methods, and cell proliferation assays. Three-dimensional structures of free IL-7, free unglycosylated and glycosylated IL-7R alpha, and complexes of IL-7 bound to unglycosylated and glycosylated IL-7R alpha will be determined using x-ray crystallography or NMR spectroscopy. Our understanding of the binding determinants for the IL-7-receptor interaction will be used to engineer novel peptide and protein antagonists using rational protein design and phage display techniques. The long-term goal of this research involves development of a structural energetic model to explain the normal and aberrant IL-7 signaling mechanisms and the generation of new therapeutic peptides/proteins to treat the many deficiencies and diseases associated with impaired IL-7 signaling. Public Health Relevance Statement: This research proposal will focus on the structural, energetic, and cell biological studies of the interaction between human interleukin-7 and its receptor, interleukin-7 receptor alpha. Our understanding of the binding determinants for the IL-7-receptor interaction will be used to engineer novel peptide and protein antagonists using rational protein design and phage display techniques. The long-term goal of this research involves development of a structural energetic model to explain the normal and aberrant IL-7 signaling mechanisms and the generation of new therapeutic peptides/proteins to treat the many deficiencies and diseases associated with impaired human IL-7 signaling.


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: 2014 ( Subtotal = $0 )
2014	2012	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	7	4/2/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $294,030 )
2012	2012	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	7	1/30/2012	NON-COMPETING CONTINUATION	$294,030
														Subtotal = $294,030

Issue Date FY: 2011 ( Subtotal = $294,030 )
2011	2011	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	6	12/14/2010	NON-COMPETING CONTINUATION	$267,300
2011	2011	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	6	6/9/2011	NON-COMPETING CONTINUATION	$26,730
														Subtotal = $294,030

Issue Date FY: 2010 ( Subtotal = $297,000 )
2010	2010	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	12/24/2009	NON-COMPETING CONTINUATION	$270,000
2010	2010	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	003	5	6/17/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$213,980
2010	2010	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	4	6/17/2010	NON-COMPETING CONTINUATION	-$213,980
2010	2010	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	4	4/30/2010	NON-COMPETING CONTINUATION	$27,000
														Subtotal = $297,000

Issue Date FY: 2009 ( Subtotal = $399,400 )
2009	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	004	3	9/15/2009	NON-COMPETING CONTINUATION	$99,400
2009	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	003	3	6/8/2009	NON-COMPETING CONTINUATION	$30,000
2009	2009	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	002	3	12/25/2008	NON-COMPETING CONTINUATION	$270,000
2009	2008	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	12/22/2008	NEW	-$139,500
2009	2008	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	001	2	12/22/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$139,500
														Subtotal = $399,400

Issue Date FY: 2008 ( Subtotal = $290,000 )
2008	2008	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	1/8/2008	NEW	$290,000
														Subtotal = $290,000

Grand Total All Awards = $1,574,460

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Molecular Recognition Studies of the Interleukin-7 Pathway

Award Number: R01AI072142

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: 01/15/2008

PERIOD OF PERFORMANCE END DATE: 12/31/2012

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