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HOMEOSTASIS OF THE ER IN DIFFERENTIATING B-CELLS

Award Number: R01GM061970
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: 06/01/2000
PERIOD OF PERFORMANCE END DATE: 06/30/2014

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HOMEOSTASIS OF THE ER IN DIFFERENTIATING B-CELLS - DESCRIPTION (provided by applicant): The long-term goal of this research program is to delineate mechanisms that regulate homeostasis of the endoplasmic reticulum (ER) in B-lymphocytes and to understand how these same mechanisms influence the fate of activated B-cells. A link exists between the supply of phosphatidylcholine (PtdCho), the most abundant phospholipid in cellular membranes, and unfolded protein response (UPR) signaling pathway. XBP1(S), a transcription factor generated by the UPR, is required for normal antibody production, maximal increases in total PtdCho and ER expansion in stimulated B-cells. Another UPR transcription factor, ATF61, also has the ability to induce PtdCho synthesis and ER expansion. Deletion of CCT1, the rate-limiting enzyme in PtdCho synthesis, markedly diminishes PtdCho production in activated B-cells. This correlates with accelerated induction of XBP1(S) and IgM secretion, but little production of other antibody isotypes. Therefore, we hypothesize that PtdCho supply can influence the fate of activated B-cells by interfacing with the UPR to promote PtdCho synthesis and drive differentiation of antibody-secreting B-cells. The project will focus on four specific aims and utilize gene knockout mouse models, cell culture systems and a combination of molecular, biochemical and cellular techniques. In aim 1, experiments will address the mechanism by which XBP1(S) up-regulates PtdCho supply in activated B-cells. In aim 2, studies will assess the contributions of ATF61 to the regulation of PtdCho synthesis and ER expansion in activated B-cells. In aim 3, experiments will address how a limited PtdCho supply at distinct stages of the B-cell response affects B-cell function and fate in vivo. In aim 4, the mechanism linking PtdCho supply to UPR activation will be explored. Experiments will assess how reduced levels of PtdCho affect ER function and protein transport in the secretory pathway. Antibody-mediated autoimmune disorders such as lupus and B-cell cancers like multiple myeloma are devastating diseases, underscoring the need to identify novel regulatory mechanisms in B-cells that might provide new targets for drug design. The UPR is also involved in many other physiologically significant processes including tumor progression and proper function of the pancreas and liver. Understanding how the UPR works in normal cellular processes is necessary for rational exploration of drugs to modulate this pathway in disease states.


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: 2013 ( Subtotal = $305,019 )
2013	2013	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Biomedical Research and Research Training	000	14	7/5/2013	NON-COMPETING CONTINUATION	$305,019
														Subtotal = $305,019

Issue Date FY: 2012 ( Subtotal = $316,082 )
2012	2012	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Biomedical Research and Research Training	000	13	6/27/2012	NON-COMPETING CONTINUATION	$316,082
														Subtotal = $316,082

Issue Date FY: 2011 ( Subtotal = $316,082 )
2011	2011	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Biomedical Research and Research Training	000	12	7/20/2011	NON-COMPETING CONTINUATION	$316,082
														Subtotal = $316,082

Issue Date FY: 2010 ( Subtotal = $319,185 )
2010	2010	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Biomedical Research and Research Training	000	11	8/30/2010	COMPETING CONTINUATION	$319,185
														Subtotal = $319,185

Issue Date FY: 2009 ( Subtotal = $58,723 )
2009	2009	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Trans-NIH Recovery Act Research Support	000	10	9/24/2009	SUPPLEMENT FOR EXPANSION	$58,723
														Subtotal = $58,723

Issue Date FY: 2008 ( Subtotal = $278,765 )
2008	2008	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Biomedical Research and Research Training	000	10	6/2/2008	NON-COMPETING CONTINUATION	$278,765
														Subtotal = $278,765

Issue Date FY: 2007 ( Subtotal = $271,553 )
2007	2007	UNIVERSITY OF SOUTH ALABAMA	307 UNIVERSITY BOULEVARD	MOBILE	AL	36688	MOBILE	USA	Biomedical Research and Research Training	000	9	8/13/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$244,524
2007	2007	LOYOLA UNIVERSITY MEDICAL CENTER	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Biomedical Research and Research Training	000	8	5/30/2007	NON-COMPETING CONTINUATION	$27,029
														Subtotal = $271,553

Issue Date FY: 2006 ( Subtotal = $290,021 )
2006	2006	LOYOLA UNIVERSITY MEDICAL CENTER	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Biomedical Research and Research Training	000	7	5/30/2006	NON-COMPETING CONTINUATION	$290,021
														Subtotal = $290,021

Issue Date FY: 2005 ( Subtotal = $297,000 )
2005	2005	LOYOLA UNIVERSITY MEDICAL CENTER							Biomedical Research and Research Training	000	6	3/11/2005	COMPETING CONTINUATION	$297,000
														Subtotal = $297,000

Issue Date FY: 2004 ( Subtotal = $212,800 )
2004	2004	LOYOLA UNIVERSITY MEDICAL CENTER							Biomedical Research and Research Training	000	5	4/23/2004	NON-COMPETING CONTINUATION	$212,800
														Subtotal = $212,800

Issue Date FY: 2003 ( Subtotal = $212,800 )
2003	2003	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Biomedical Research and Research Training	000	4	5/29/2003	NON-COMPETING CONTINUATION	$212,800
														Subtotal = $212,800

Issue Date FY: 2002 ( Subtotal = $212,800 )
2002	2002	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Biomedical Research and Research Training	000	3	5/31/2002	NON-COMPETING CONTINUATION	$212,800
														Subtotal = $212,800

Issue Date FY: 2001 ( Subtotal = $210,373 )
2001	2001	LOYOLA UNIVERSITY MEDICAL CENTER	2160 SOUTH FIRST AVENUE	MAYWOOD	IL	60153	COOK	USA	Biomedical Research and Research Training	000	2	5/28/2001	NON-COMPETING CONTINUATION	$210,373
														Subtotal = $210,373

Issue Date FY: 2000 ( Subtotal = $209,403 )
2000	2000	LOYOLA UNIVERSITY OF CHICAGO	820 N MICHIGAN AVENUE	CHICAGO	IL	60611	COOK	USA	Biomedical Research and Research Training	000	1	5/26/2000	NEW	$209,403
														Subtotal = $209,403

Grand Total All Awards = $3,510,606

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HOMEOSTASIS OF THE ER IN DIFFERENTIATING B-CELLS

Award Number: R01GM061970

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: 06/01/2000

PERIOD OF PERFORMANCE END DATE: 06/30/2014

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