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CYTOKINES AND INFLAMMATORY BOWEL DISEASE

Award Number: R37DK042191
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2009
PERIOD OF PERFORMANCE END DATE: 06/30/2010

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CYTOKINES AND INFLAMMATORY BOWEL DISEASE - There is increasing evidence that cytokines, in general, and tumor necrosis factor (TNF), in particular, may play a key role in the pathogenesis of Crohn's disease (CD), one of the known idiopathic inflammatory bowel diseases (IBD)s. The most compelling evidence supporting the role of TNF in CD comes from recent studies using single dose infusions of anti- TNF monoclonal antibody in patients with active, therapy-refractory disease. In the majority of treated patients, TNF blockade resulted in decreased disease activity and sustained remission. Increasingevidence suggests that these effects are immunologically mediated. However, the precise mechanism(s) of TNF's actions in CD and the relationshipbetween TNF and immuneeffector cells remains unclear. Our preliminary findings provide direct evidence that a specific deregulation of TNF synthesis in mice, i.e. targeted deletion of AU-rich elements (AARE) in the in the 3' UTR region of the TNF gene, results in systemic TNF overexpression and triggers a CD-like intestinal phenotype that closely resembles the human disease. Therefore, the central hypothesis of this proposal is that TNF plays a crucial pathogenic role in CD by affecting primary immunoregulatory mechanisms, which result in the gut inflammatory changes characteristic of this disease. In this context, anti-TNF treatment may not directly target the effector functions of TNF but may, rather, interfere with these key immunologicalmechanisms. This hypothesis will be tested in TNFAARE mice by investigatingthe following 4 specific aims: 1) Characterize the features of chronic intestinal inflammation. The clinical phenotype, histological features, as well as the specific cytokine profiles will be investigated in our TNFAAR1; colony at UVA. 2) Define the role of the immune response in the development of intestinal inflammation. A series of cross-breeding studies, T-cell adoptive transfer as well as bone marrow chimera experiments will be performed to precisely define the role of T-cell subsets, B cells and other immunocytes in mediatingthe observed CD-like pathology. 3) Examine the role of the two TNF receptors in mediating intestinal inflammation. The expression of TNF receptor isoforms in intestinal tissues as well as isolated mucosal cells will be studied by multipletechniques. In addition, the AARE mutation will be introduced into TNFRI-or TNFRII-deficient mice to asssss the relative contributionof the two TNF receptors to TNF-mediated gut inflammation. Finally, we will study the effects of gut-specific reactivation of the TNFRI and/or TNFRII in double mutant TNFAAIUVTNFR ' mice. 4) Determine whether gut-specific TNF overexpression is sufficient to induce chronic intestinal inflammation. Using an intestinal-specificpromoter and Cre-loxP technology, we will compare the effects of systemic versus local TNF overexpression on the development of chronic intestinal inflammation in TNFAARH mice. The ultimate goal of the present research proposal is to define the precise mechanism(s) of TNF-induced CD in order to develop specific treatment modalities aimed at modifying the natural course of this devastating disease.


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: 2009 ( Subtotal = $59,540 )
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Trans-NIH Recovery Act Research Support	002	22	9/9/2009	SUPPLEMENT FOR EXPANSION	$59,540
2009	2008	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	21	4/10/2009	NON-COMPETING CONTINUATION	-$103,206
2009	2008	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	4/10/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$103,206
														Subtotal = $59,540

Issue Date FY: 2008 ( Subtotal = $467,829 )
2008	2008	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	21	6/11/2008	NON-COMPETING CONTINUATION	$467,829
														Subtotal = $467,829

Issue Date FY: 2007 ( Subtotal = $465,778 )
2007	2007	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	20	7/2/2007	NON-COMPETING CONTINUATION	$465,778
														Subtotal = $465,778

Issue Date FY: 2006 ( Subtotal = $468,091 )
2006	2006	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	19	7/17/2006	NON-COMPETING CONTINUATION	$468,091
														Subtotal = $468,091

Issue Date FY: 2005 ( Subtotal = $467,821 )
2005	2005	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	18	7/4/2005	NON-COMPETING CONTINUATION	$467,821
														Subtotal = $467,821

Issue Date FY: 2004 ( Subtotal = $516,529 )
2004	2004	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	17	9/2/2004	EXTENSION WITH OR WITHOUT FUNDS	$516,529
														Subtotal = $516,529

Issue Date FY: 2003 ( Subtotal = $341,545 )
2003	2003	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	16	6/9/2003	NON-COMPETING CONTINUATION	$341,545
														Subtotal = $341,545

Issue Date FY: 2002 ( Subtotal = $332,758 )
2002	2002	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	15	6/11/2002	NON-COMPETING CONTINUATION	$332,758
														Subtotal = $332,758

Issue Date FY: 2001 ( Subtotal = $323,066 )
2001	2001	UNIVERSITY OF VIRGINIA	PO BOX 9003	CHARLOTTESVILLE	VA	22906	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	14	6/13/2001	NON-COMPETING CONTINUATION	$323,066
														Subtotal = $323,066

Issue Date FY: 2000 ( Subtotal = $313,659 )
2000	2000	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	13	7/31/2000	NON-COMPETING CONTINUATION	$313,659
														Subtotal = $313,659

Issue Date FY: 1999 ( Subtotal = $316,522 )
1999	1999	UNIVERSITY OF VIRGINIA	PO BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Digestive Diseases and Nutrition Research	000	12	9/24/1999	COMPETING CONTINUATION	$316,522
														Subtotal = $316,522

Grand Total All Awards = $4,073,138

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CYTOKINES AND INFLAMMATORY BOWEL DISEASE

Award Number: R37DK042191

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2009

PERIOD OF PERFORMANCE END DATE: 06/30/2010

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