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Inhibition of STAT3 and inflammatory cytokine production

Award Number: R01AI044938
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: 09/30/1999
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Inhibition of STAT3 and inflammatory cytokine production - Macrophages play important roles in tissue homeostasis, host defense, response to injury, tissue repair, and resolution of inflammation. The long term goals of this project are to understand how macrophage functional phenotypes are regulated to balance host defense and inflammation with homeostatic functions that resolve inflammation and restore tissue integrity. An associated goal is to therapeutically modulate macrophages to promote tissue repair while minimizing inflammatory pathology. Macrophages assume various phenotypes dependent on ontogeny, tissue-specific factors, epigenetic programming, and (micro)environmental challenges. Inflammatory macrophages produce cytokines such as TNF and IL-1 that are important for host defense and inflammation, while reparative and pro-resolution macrophages produce suppressive and growth factors such as IL-10, VEGF and PDGF important for tissue repair, wound healing and resolution of inflammation. Recent high dimensional analyses using flow/mass cytometry and single cell RNA sequencing (scRNAseq) have revealed distinct macrophage populations and functional phenotypes in different tissues and disease states. Wound healing typically progresses through inflammatory, tissue repair, and tissue remodeling stages. Both inflammatory and repair phases, and a well-regulated balance and transition between them, are important for effective wound healing. Excessive inflammation, such as occurs in chronic TNF-driven inflammatory diseases such as rheumatoid arthritis (RA), results in ineffective repair and chronic wounds. Immune cells including macrophages play important roles in the first two phases of wound healing, and modulation of macrophage function to improve tissue repair is an emerging therapeutic strategy. In the previous project period we investigated mechanisms of crossregulation between the inflammatory factor TNF and the repair factor IL-4, using primary human macrophages and mouse models of wound healing. While IL-4 suppressed components of the TNF inflammatory response, the two cytokines synergized to induce genes associated with resolution of inflammation. The balance between an inflammatory and reparative macrophage phenotype was regulated in part by SREBP transcription factors. Myeloid inactivation or pharmacological inhibition of SREBPs accelerated wound healing. scRNAseq identified novel macrophage populations induced by injury and associated with tissue repair. These data provide insights into mechanisms that regulate the transition from inflammation to repair, and support our overarching hypothesis that selective modulation of the immune system can be utilized to improve tissue repair. In this project we will investigate mechanisms that regulate the balance and transition between inflammation and tissue repair. We anticipate that our studies will yield insights that can be used to develop novel therapeutic strategies to enhance wound healing and restore tissue function.


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 = $431,650 )
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	000	25	1/21/2025	NON-COMPETING CONTINUATION	$431,650
														Subtotal = $431,650

Issue Date FY: 2024 ( Subtotal = $445,000 )
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	24	5/24/2024	NON-COMPETING CONTINUATION	$44,500
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	24	1/24/2024	NON-COMPETING CONTINUATION	$400,500
														Subtotal = $445,000

Issue Date FY: 2023 ( Subtotal = $445,000 )
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	23	1/11/2023	NON-COMPETING CONTINUATION	$445,000
														Subtotal = $445,000

Issue Date FY: 2022 ( Subtotal = $444,252 )
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	001	22	1/28/2022	NON-COMPETING CONTINUATION	$0
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	22	1/20/2022	NON-COMPETING CONTINUATION	$445,000
2022	2019	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	003	20	6/29/2022	NON-COMPETING CONTINUATION	-$748
2022	2018	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	004	19	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2017	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Allergy and Infectious Diseases Research	002	18	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $444,252

Issue Date FY: 2021 ( Subtotal = $445,000 )
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	001	21	1/28/2021	COMPETING CONTINUATION	$445,000
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	000	20	1/27/2021	NON-COMPETING CONTINUATION	$0
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	002	20	9/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $445,000

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	4/20/2019	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	3/20/2018	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	4/4/2017	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	4/19/2016	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	001	16	4/29/2015	COMPETING CONTINUATION	$440,000
2015	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	4/28/2015	NON-COMPETING CONTINUATION	$0
														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	3/28/2014	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	000	14	4/9/2013	NON-COMPETING CONTINUATION	$390,926
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	6/4/2013	NON-COMPETING CONTINUATION	$17,375
														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	4/16/2012	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	000	12	4/19/2011	NON-COMPETING CONTINUATION	$394,875
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	6/9/2011	NON-COMPETING CONTINUATION	$39,488
														Subtotal = $434,363

Issue Date FY: 2010 ( Subtotal = $437,916 )
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	5/10/2010	COMPETING CONTINUATION	$437,916
														Subtotal = $437,916

Issue Date FY: 2009 ( Subtotal = $316,256 )
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	1/26/2009	NON-COMPETING CONTINUATION	$284,631
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	6/30/2009	NON-COMPETING CONTINUATION	$31,625
														Subtotal = $316,256

Issue Date FY: 2008 ( Subtotal = $316,256 )
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	2/8/2008	NON-COMPETING CONTINUATION	$316,256
														Subtotal = $316,256

Issue Date FY: 2007 ( Subtotal = $322,381 )
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	$322,381
														Subtotal = $322,381

Issue Date FY: 2006 ( Subtotal = $332,010 )
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	$332,010
														Subtotal = $332,010

Issue Date FY: 2005 ( Subtotal = $289,000 ) (Continued on the next page)
Grand Total All Awards = $9,206,689

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Inhibition of STAT3 and inflammatory cytokine production

Award Number: R01AI044938

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: 09/30/1999

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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