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UBIQUITINATION OF TOLL-LIKE RECEPTOR SIGNALSOME

Award Number: R01GM069652
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2005
PERIOD OF PERFORMANCE END DATE: 12/31/2010

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UBIQUITINATION OF TOLL-LIKE RECEPTOR SIGNALSOME - DESCRIPTION (provided by applicant): Innate immunity is the first line of defense against microbial invasions in the human body. Innate immune cells recognize invading microorganisms via a set of receptors termed Toll-like receptors (TLRs). Activation of TLRs triggers rapid innate immune responses and subsequently leads to effective adaptive immune responses to combat the foreign invaders. The innate immune responses are mediated by expression of a variety of immune response genes and synthesis of inflammatory mediators such as cytokines, lipid secondary metabolites, and reactive oxygen species. Dysfunctional responses, either failure to respond or hyperresponsiveness, may lead to both acute and chronic immunodeficiency and inflammatory diseases. Therefore, the intensity and duration of TLR activation must be tightly controlled. We have identified a novel TLR interacting protein termed TriadSA which is a member of a group of related proteins resulting from alternative splicing of the Triads gene. The TriadSA is an E3 ubiquitin-protein ligase that promotes ubiquitination and degradation of several TLRs and their downstream signaling molecules. Overexpression of TriadSA blocks TLR ligand-induced NF-kappaB activation in cells. Conversely, reduction in endogenous TriadSA by siRNA increases TLR expression and enhances TLR activation. These results suggest that TriadSA is a component of an endogenous control mechanism for TLR expression and activation. In this project, we will focus on three specific aims to gain more insight into its functions. We will: (1) perform structure-functional studies to determine the binding motif within the TLRs for TriadSA, (2) determine the functions and molecular mechanisms of TriadSA in TLR ligand-induced cellular responses, and (3) determine the roles of TriadSA in LPS induced tolerance and septic shock. Completion of this project will help us to elucidate the control mechanisms of TLR activation, and provide information for potential therapeutic strategies in diseases caused by loss of control of TLR activation.


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	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	7	12/28/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $395,135 )
2009	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	005	7	7/30/2009	SUPPLEMENT FOR EXPANSION	$96,379
2009	2009	BURNHAM INSTITUTE FOR MEDICAL RESEARCH	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	004	7	7/8/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$234,569
2009	2009	SIDNEY KIMMEL CANCER CENTER	10905 Road To The Cure	San Diego	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	003	6	7/8/2009	NON-COMPETING CONTINUATION	-$239,482
2009	2009	SIDNEY KIMMEL CANCER CENTER	10905 Road To The Cure	San Diego	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	002	6	4/21/2009	NON-COMPETING CONTINUATION	$295,833
2009	2008	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	11/25/2008	NON-COMPETING CONTINUATION	-$270,000
2009	2008	SIDNEY KIMMEL CANCER CENTER	10905 Road To The Cure	San Diego	CA	92121	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	11/25/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$277,836
														Subtotal = $395,135

Issue Date FY: 2008 ( Subtotal = $287,489 )
2008	2008	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	4/11/2008	NON-COMPETING CONTINUATION	$287,489
														Subtotal = $287,489

Issue Date FY: 2007 ( Subtotal = $282,027 )
2007	2007	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	4/20/2007	NON-COMPETING CONTINUATION	$282,027
														Subtotal = $282,027

Issue Date FY: 2006 ( Subtotal = $290,450 )
2006	2006	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	4/24/2006	NON-COMPETING CONTINUATION	$290,450
														Subtotal = $290,450

Issue Date FY: 2005 ( Subtotal = $297,440 )
2005	2005	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	4/22/2005	NEW	$297,440
														Subtotal = $297,440

Grand Total All Awards = $1,552,541

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UBIQUITINATION OF TOLL-LIKE RECEPTOR SIGNALSOME

Award Number: R01GM069652

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2005

PERIOD OF PERFORMANCE END DATE: 12/31/2010

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