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REGULATION OF SIGNALING EVENTS IN SEPTIC LEUKOCYTES

Award Number: R01AI050089
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 03/15/2002
PERIOD OF PERFORMANCE END DATE: 02/28/2007

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REGULATION OF SIGNALING EVENTS IN SEPTIC LEUKOCYTES - DESCRIPTION (provided by applicant): Many products of microbial pathogens activate the cellular innate immune response and induce expression of both pro-inflammatory cytokines such as interleukin-1beta (L-1beta), as well as anti-inflammatory cytokines such as secreted interleukin-1 receptor antagonist (sIL-1RA). However, prolonged exposures to microbial products such as LPS during infection result in a refractory state called endotoxin tolerance. When stimulated ex vivo with additional doses of endotoxin, tolerant leukocytes exhibit an adaptive immune response reflected by decreased production of pro-inflammatory cytokines and continued production of anti-inflammatory cytokines. The imbalance of anti- and pro- inflammatory cytokine production is characteristic of blood leukocytes from septic patients. Toll-like receptors (TLRs) mediate LPS and other microbial induced cytokine gene expression. We observe that the interleukin-1 receptor-associated kinase (IRAK), which lies proximal in the LPS-TLR signaling pathway, is inactivated and reduced in quantity upon prolonged LPS stimulation. The disruption of IRAK may contribute to the repressed transcription of LPS responsive cytokine genes in tolerant leukocytes. Despite the disrupted TLR signaling and reduced cytokine gene transcription, LPS can still induce several non-cytokine gene transcriptions with unknown mechanism. In addition, LPS can also induce anti-inflammatory cytokine sIL-1RA protein translation in tolerant leukocytes. We observe that the LPS-inducible phosphatidylinositol-3 kinase-dependent pathway is NOT disrupted in the tolerant leukocytes, and selectively contributes to the translation of sIL-1RA protein, despite reduction in its transcription. Aim 1. We plan to examine the mechanism of LPS-induced IRAK degradation. The protein kinase responsible for IRAK phosphorylation and degradation will be determined. Aim 2. We plan to examine the regulation of IRAK2 and IRAKM. Specifically, we will test whether IRAK2/M responds to microbial product challenges other than LPS. In addition, we will ask whether they participate in LPS-induced non-cytokine gene transcription (such as metalloproteinase-9) in tolerant leukocytes. Aim 3. We will study the regulation of PI3 kinase in LPS treated normal and tolerant cells. PI3 kinase has been shown to be upregulated in both normal and tolerant leukocytes. We plan to identify the specific catalytic subunit(s) of PI3 kinase that is (are) activated by LPS, and responsible for elevated sIL-1RA translation. The mechanism of PI3 kinase enhanced translation will be studied.


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: 2006 ( Subtotal = $294,903 )
2006	2006	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	6	2/27/2006	NON-COMPETING CONTINUATION	$294,903
														Subtotal = $294,903

Issue Date FY: 2005 ( Subtotal = $302,000 )
2005	2005	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	460 TURNER STREET, SUITE 306	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	5	10/14/2005	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$302,000
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	4	3/2/2005	NON-COMPETING CONTINUATION	$0
														Subtotal = $302,000

Issue Date FY: 2004 ( Subtotal = $287,333 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	3	2/25/2004	NON-COMPETING CONTINUATION	$287,333
														Subtotal = $287,333

Issue Date FY: 2003 ( Subtotal = $313,000 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	2		OTHER REVISION	$313,000
														Subtotal = $313,000

Issue Date FY: 2002 ( Subtotal = $313,334 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Allergy and Infectious Diseases Research	000	1	3/2/2002	NEW	$313,334
														Subtotal = $313,334

Grand Total All Awards = $1,510,570

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REGULATION OF SIGNALING EVENTS IN SEPTIC LEUKOCYTES

Award Number: R01AI050089

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 03/15/2002

PERIOD OF PERFORMANCE END DATE: 02/28/2007

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