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Activation of Macrophages in Human Autoimmune Diseases

Award Number: R01AI046712
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: 03/01/2000
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Activation of Macrophages in Human Autoimmune Diseases - Macrophages play a key role in the pathogenesis of various autoimmune and rheumatic diseases. An important mechanism by which activated macrophages contribute to disease pathogenesis is production of inflammatory cytokines such as TNF, IL-1 and IL-6. These cytokines are canonical NF-B target genes and validated therapeutic targets. The long term goals of this project are to understand how inflammatory macrophage activation is regulated, with the associated goal of developing new therapies that selectively suppress pathogenic macrophage functions, while preserving homeostatic functions and host defense. Type I IFNs and IFN- are important regulators of immunity and inflammation. IFNs activate the JAK- STAT signaling pathway to induce canonical interferon-stimulated genes (ISGs). Expression of IFN target genes (termed an ‘IFN signature’) is one of the most prominent molecular pathways activated in several autoimmune diseases including RA, lupus nephritis, and macrophage activation syndrome (MAS) (and related familial hemophagocytic lymphohistiocytosis (fHLH)). IFNs are clearly pathogenic in monogenic ‘interferonopathies’ and fHLH, where patients are responsive to JAK inhibitors and IFN- blockade. JAK inhibitors, which target IFNs amongst other cytokines, are effective in RA and are being tested in SLE. Although IFNs do not directly activate pathogenic non-ISG inflammatory NF-B target genes such as TNF, IL1B and IL6, they potentiate induction of these genes by TNF and TLRs. This supports the possibility that the therapeutic efficacy of IFN blockade or Jak inhibitors may be mediated at least in part by direct suppression of inflammatory cytokine production in macrophages. In accord with this notion, JAK inhibitors decrease inflammatory responses and cytokines in RA patients, primed human macrophages, RA synovial macrophages and tissue explants, and in preclinical models of arthritis and MAS/fHLH. In the previous project period we found that IFN-JAK-STAT signaling induces chromatin remodeling at inflammatory NF-B target genes to make these genes hyper-responsive to inflammatory signals and resistant to suppression. IFNs also selectively suppressed components of the macrophage response to the suppressive cytokine IL-10 by deactivating enhancers. These data provide insights into pathways that connect IFN-JAK-STAT signaling to inflammatory NF-B target genes and support our overarching hypothesis that IFNs help drive inflammatory non-ISG gene expression via chromatin-based mechanisms. In this project we will investigate epigenetic mechanisms by which IFNs drive macrophage activation and expression of pathogenic NF-B target genes such as TNF, IL1B and IL6, and mechanisms by which JAK inhibitors suppress these genes. We anticipate that our studies will yield insights that can be used to develop novel therapeutic strategies to suppress inflammatory responses, and help understand how epigenetic mechanisms can contribute to poor efficacy of therapies that target upstream signaling pathways.


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 = $3,071,328 )
2025	2025	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	26	8/13/2025	COMPETING CONTINUATION	$3,071,328
2025	2024	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	25	8/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,071,328

Issue Date FY: 2024 ( Subtotal = $408,129 )
2024	2024	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	25	5/24/2024	NON-COMPETING CONTINUATION	$40,813
2024	2024	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	25	2/20/2024	NON-COMPETING CONTINUATION	$367,316
														Subtotal = $408,129

Issue Date FY: 2023 ( Subtotal = $409,203 )
2023	2023	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	24	4/6/2023	NON-COMPETING CONTINUATION	$409,203
														Subtotal = $409,203

Issue Date FY: 2022 ( Subtotal = $410,245 )
2022	2022	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	23	2/11/2022	NON-COMPETING CONTINUATION	$410,245
														Subtotal = $410,245

Issue Date FY: 2021 ( Subtotal = $411,257 )
2021	2021	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	22	3/25/2021	NON-COMPETING CONTINUATION	$411,257
2021	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	002	21	6/7/2021	COMPETING CONTINUATION	$109,553
2021	2019	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	20	6/7/2021	NON-COMPETING CONTINUATION	-$109,553
														Subtotal = $411,257

Issue Date FY: 2020 ( Subtotal = $412,240 )
2020	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	21	1/10/2020	COMPETING CONTINUATION	$408,080
2020	2020	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	21	1/14/2020	COMPETING CONTINUATION	$4,160
														Subtotal = $412,240

Issue Date FY: 2019 ( Subtotal = $440,000 )
2019	2019	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	20	2/22/2019	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2018 ( Subtotal = $440,000 )
2018	2018	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	19	3/1/2018	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2017 ( Subtotal = $440,000 )
2017	2017	THE HOSPITAL FOR SPECIAL SURGERY FUND INC	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	18	2/15/2017	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2016 ( Subtotal = $440,000 )
2016	2016	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	17	2/22/2016	NON-COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2015 ( Subtotal = $440,000 )
2015	2015	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	16	1/29/2015	COMPETING CONTINUATION	$440,000
														Subtotal = $440,000

Issue Date FY: 2014 ( Subtotal = $434,363 )
2014	2014	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	15	2/21/2014	NON-COMPETING CONTINUATION	$434,363
														Subtotal = $434,363

Issue Date FY: 2013 ( Subtotal = $408,301 )
2013	2013	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	14	6/5/2013	NON-COMPETING CONTINUATION	$17,375
2013	2013	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	14	2/11/2013	NON-COMPETING CONTINUATION	$390,926
														Subtotal = $408,301

Issue Date FY: 2012 ( Subtotal = $434,363 )
2012	2012	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	13	2/20/2012	NON-COMPETING CONTINUATION	$434,363
														Subtotal = $434,363

Issue Date FY: 2011 ( Subtotal = $434,363 )
2011	2011	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	12	6/8/2011	NON-COMPETING CONTINUATION	$39,488
2011	2011	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	12	2/24/2011	NON-COMPETING CONTINUATION	$394,875
														Subtotal = $434,363

Issue Date FY: 2010 ( Subtotal = $437,709 )
2010	2010	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	11	2/25/2010	COMPETING CONTINUATION	$209
2010	2010	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	11	2/23/2010	COMPETING CONTINUATION	$437,500
														Subtotal = $437,709

Issue Date FY: 2009 ( Subtotal = $355,790 )
2009	2009	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	001	10	6/11/2009	NON-COMPETING CONTINUATION	$35,580
2009	2009	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	10	2/13/2009	NON-COMPETING CONTINUATION	$320,210
														Subtotal = $355,790

Issue Date FY: 2008 ( Subtotal = $355,790 )
2008	2008	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	9	2/11/2008	NON-COMPETING CONTINUATION	$355,790
														Subtotal = $355,790

Issue Date FY: 2007 ( Subtotal = $362,680 )
2007	2007	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	8	2/27/2007	NON-COMPETING CONTINUATION	$362,680
														Subtotal = $362,680

Issue Date FY: 2006 ( Subtotal = $373,512 )
2006	2006	HOSPITAL FOR SPECIAL SURGERY (THE)	525 EAST 71ST STREET, 2ND FLR	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	000	7	2/15/2006	NON-COMPETING CONTINUATION	$373,512
														Subtotal = $373,512

Issue Date FY: 2005 ( Subtotal = $382,500 ) (Continued on the next page)
Grand Total All Awards = $12,497,201

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Activation of Macrophages in Human Autoimmune Diseases

Award Number: R01AI046712

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: 03/01/2000

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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