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TOLL-LIKE RECEPTOR SIGNALING IN THE PATHOGENESIS AND PREVENTION OF PREMATURITY

Award Number: R01HD056118
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2008
PERIOD OF PERFORMANCE END DATE: 06/30/2013

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TOLL-LIKE RECEPTOR SIGNALING IN THE PATHOGENESIS AND PREVENTION OF PREMATURITY - DESCRIPTION (provided by applicant): The innate immune system recognizes pathogens via the interaction of molecular constituents of microorganisms with specialized pattern recognition molecules on host cells known as toll-like receptors (TLRs). Each of the 12 known toll-like receptors engages a different set of pathogenic markers, thereby recognizing in total a large variety of microorganisms. This engagement leads to activation and induction of inflammatory mediators via only two major intracellular pathways, known as the myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling pathways. The objective of this proposal is to test the hypothesis that toll-like receptor signaling via the MyD88-dependent signal transduction pathway is an essential and modifiable mediator of pathogen-induced preterm labor. This hypothesis will be tested in a mouse model by first (Specific Aim #1) characterizing the roles of the MyD88-dependent and -independent pathways in pathogen-induced labor using peptidoglycan (a TLR-2 ligand derived from Gram positive bacterial cell walls) and group B beta-hemolytic streptococcus (GBBS, a Gram positive organism associated with preterm labor and neonatal sepsis). Mutant mice lacking either TLR-2 or MyD88 will be used to define the roles of these proteins in pathogen-induced labor. In Specific Aim #2 the capacity of a negative regulator of MyD88 (a splice variant known as MyD88s) to prevent MyD88-dependent preterm birth will be tested. A new method of delivering exogenous proteins intracellularly (TAT-fusion proteins) will be used to ferry MyD88s into the gestational compartment. Finally, in Specific Aim #3 we will take advantage of a novel observation made since the first submission of this application, namely that E. coli-induced labor has an exclusive requirement for MyD88. Dissection of the respective roles of mothers and fetuses in signaling for E. coli induced labor will be conducted using pregnancies in which maternal and fetal MyD88 genotypes differ in informative ways. PUBLIC HEALTH RELEVANCE: Preterm birth affects over 12% of all deliveries in the U.S., or approximately 480,000 babies annually, and continues to be the most important cause of neonatal illness and death in developed countries. Fifty percent or more of unexplained cases of preterm birth are related to infection. The incidence of preterm delivery continues to rise in the U.S., a fact that reflects continuing deficiencies in our knowledge of the causes and mechanisms of parturition.


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: 2012 ( Subtotal = $307,989 )
2012	2012	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Child Health and Human Development Extramural Research	000	5	6/22/2012	NON-COMPETING CONTINUATION	$307,989
														Subtotal = $307,989

Issue Date FY: 2011 ( Subtotal = $300,567 )
2011	2011	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Child Health and Human Development Extramural Research	000	4	7/22/2011	NON-COMPETING CONTINUATION	$300,567
														Subtotal = $300,567

Issue Date FY: 2010 ( Subtotal = $529,720 )
2010	2010	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Child Health and Human Development Extramural Research	000	3	6/18/2010	NON-COMPETING CONTINUATION	$318,171
2010	2010	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Trans-NIH Recovery Act Research Support	001	3	8/25/2010	SUPPLEMENT FOR EXPANSION	$211,549
														Subtotal = $529,720

Issue Date FY: 2009 ( Subtotal = $324,063 )
2009	2009	NORTHSHORE UNIVERSITY HEALTHSYSTEM RESEARCH INSTITUTE	1001 UNIVERSITY PLACE	EVANSTON	IL	60201	COOK	USA	Child Health and Human Development Extramural Research	000	2	7/22/2009	NON-COMPETING CONTINUATION	$324,063
														Subtotal = $324,063

Issue Date FY: 2008 ( Subtotal = $324,063 )
2008	2008	EVANSTON NORTHWESTERN HEALTHCARE RESEARCH INSTITUTE	2650 RIDGE AVENUE	EVANSTON	IL	60201	COOK	USA	Child Health and Human Development Extramural Research	000	1	9/25/2008	NEW	$324,063
														Subtotal = $324,063

Grand Total All Awards = $1,786,402

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TOLL-LIKE RECEPTOR SIGNALING IN THE PATHOGENESIS AND PREVENTION OF PREMATURITY

Award Number: R01HD056118

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2008

PERIOD OF PERFORMANCE END DATE: 06/30/2013

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