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Characterization of SLE-susceptibility loci on mouse chromosome 1

Award Number: R01AI045050
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/1999
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Characterization of SLE-susceptibility loci on mouse chromosome 1 - Project summary Sle1, the strongest lupus susceptibility locus in the NZM2410 mouse model, is responsible for the loss of tolerance to chromatin, including the production of autoreactive CD4+ T cells. It corresponds to a cluster of loci, including Sle1a1 that enhances effector CD4+ T cell function and reduces the number and function of peripheral (p)Treg cells. Sle1a1 corresponds to the expression of Pbx1-d, a splice isoform of the transcription factor Pbx1 that lacks the DNA- and Hox-binding domains, as compared to Pbx1-b, the common isoform in lymphocytes. Pbx1-d is expressed at a higher level in CD4+ T cells from B6.Sle1a1 and NZM2410 mice, and from SLE patients, as compared to B6 mice and healthy controls (HC). Importantly, the PBX1 isoforms and the protein sequence are identical between mice and humans. In the previous cycle of funding, we showed that either Pbx1-d Tg expression in T cells or the FOXP3-specific deletion of Pbx1 impaired the maintenance of pTregs, resulting in a global CD4+ T cell activation, which increased atherogenic lesions as well as autoimmunity in dyslipidemic mice. Our work therefore established a novel role for Pbx1 to maintain Treg homeostasis. We also showed that Pbx1 expression in CD4+ T cells is the highest in Tregs, and that Pbx1-d is a dysfunctional protein through multiple mechanisms. Our work is the first to associate a specific genetic variation to the well-documented alterations in Tregs in human and mouse lupus. A SNP decreasing PBX1 expression in B cells has also been recently associated to SLE susceptibility and a B-cell specific deletion of Pbx1 enhanced B cell responses in mice. Therefore, Pbx1 represents a unique lupus susceptibility gene in both mice and humans that impairs Tregs through the over-expression of Pbx1-d and B cells through a reduced global expression. In this competitive renewal, we propose to characterize the mechanisms by which Pbx1 regulates pTreg maintenance and function at the molecular and cellular levels, and how this process is altered by the expression of lupus-susceptibility allele Pbx1-d. In addition, we propose to characterize the combined effects of a reduced Pbx1 expression in B cells and overexpression of Pbx1-d in Tregs to comprehensively define the contribution of Pbx1 to lupus susceptibility. To achieve these goals, we propose three specific aims conducted in mice as well as in PBMCs obtained from SLE patients and HCs. Aim 1. To characterize the functional consequences of Pbx1-d expression in Tregs using cellular assays with murine cells that express only Pbx1-b or Pbx1-d, and human cells based on their PBX1-D expression. Aim 2. To define the molecular pathways regulated by Pbx1 and Pbx1-d in Tregs with gene expression profiling, Pbx1 binding sites and chromatin accessibility, scRNA-Seq, and proteomics. Aim 3. To define the consequences of Pbx1-deficiency or Pbx1-d expression in Tregs combined with Pbx1 deficiency in B cells. The proposed experiments will provide for the first time a comprehensive molecular and cellular roadmap to Pbx1-d and/or a reduced Pbx1 expression leading to lupus susceptibility, as well as novel insights on the role of Pbx1 in the regulation of T and B cell functions in mice and humans.


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: 2025 ( Subtotal = $721,482 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	002	25	6/10/2025	NON-COMPETING CONTINUATION	$721,482
2025	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	24	2/24/2025	COMPETING CONTINUATION	$6,217
2025	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	23	2/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$6,217
														Subtotal = $721,482

Issue Date FY: 2024 ( Subtotal = $703,044 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	004	24	9/4/2024	COMPETING CONTINUATION	$57,932
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	003	24	7/5/2024	COMPETING CONTINUATION	$645,112
2024	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	002	23	12/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$146,228
2024	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	22	12/12/2023	NON-COMPETING CONTINUATION	-$137,225
2024	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	22	12/12/2023	SUPPLEMENT FOR EXPANSION	-$9,003
														Subtotal = $703,044

Issue Date FY: 2022 ( Subtotal = $592,038 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	002	23	7/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$592,038
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	22	7/15/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	22	7/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $592,038

Issue Date FY: 2021 ( Subtotal = $609,334 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	22	5/12/2021	NON-COMPETING CONTINUATION	$571,817
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	22	7/21/2021	SUPPLEMENT FOR EXPANSION	$37,517
														Subtotal = $609,334

Issue Date FY: 2020 ( Subtotal = $561,456 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	21	5/6/2020	NON-COMPETING CONTINUATION	$561,456
														Subtotal = $561,456

Issue Date FY: 2019 ( Subtotal = $551,272 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	20	6/5/2019	NON-COMPETING CONTINUATION	$551,272
2019	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	19	2/25/2019	COMPETING CONTINUATION	$177,824
2019	2017	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	18	2/25/2019	NON-COMPETING CONTINUATION	-$177,824
														Subtotal = $551,272

Issue Date FY: 2018 ( Subtotal = $541,633 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	19	6/20/2018	COMPETING CONTINUATION	$541,633
2018	2017	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	18	6/20/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $541,633

Issue Date FY: 2017 ( Subtotal = $478,127 )
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	18	3/27/2017	NON-COMPETING CONTINUATION	$478,127
2017	2016	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	17	1/18/2017	EXTENSION WITH OR WITHOUT FUNDS	$50,531
2017	2015	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	16	1/18/2017	NON-COMPETING CONTINUATION	-$50,531
														Subtotal = $478,127

Issue Date FY: 2016 ( Subtotal = $478,127 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	17	4/6/2016	EXTENSION WITH OR WITHOUT FUNDS	$478,127
														Subtotal = $478,127

Issue Date FY: 2015 ( Subtotal = $478,127 )
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	16	3/20/2015	NON-COMPETING CONTINUATION	$478,127
														Subtotal = $478,127

Issue Date FY: 2014 ( Subtotal = $353,053 )
2014	2014	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	15	4/23/2014	NON-COMPETING CONTINUATION	$353,053
														Subtotal = $353,053

Issue Date FY: 2013 ( Subtotal = $329,873 )
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	14	6/3/2013	COMPETING CONTINUATION	$14,164
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	14	3/1/2013	COMPETING CONTINUATION	$315,709
														Subtotal = $329,873

Issue Date FY: 2012 ( Subtotal = $424,417 )
2012	2012	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	13	4/9/2012	NON-COMPETING CONTINUATION	$424,417
														Subtotal = $424,417

Issue Date FY: 2011 ( Subtotal = $424,617 )
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	12	8/2/2011	NON-COMPETING CONTINUATION	$31,011
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	12	4/22/2011	NON-COMPETING CONTINUATION	$393,606
														Subtotal = $424,617

Issue Date FY: 2010 ( Subtotal = $424,600 )
2010	2010	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	11	4/8/2010	NON-COMPETING CONTINUATION	$424,600
														Subtotal = $424,600

Issue Date FY: 2009 ( Subtotal = $421,409 )
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	10	4/14/2009	NON-COMPETING CONTINUATION	$421,409
														Subtotal = $421,409

Issue Date FY: 2008 ( Subtotal = $410,878 )
2008	2008	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	9	2/19/2008	COMPETING CONTINUATION	$410,878
														Subtotal = $410,878

Grand Total All Awards = $10,826,935

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Characterization of SLE-susceptibility loci on mouse chromosome 1

Award Number: R01AI045050

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/1999

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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