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Targeting TGFb/IFNy-IRF8 Signaling to Modulate Monocytes and their Crosstalk with Microglia and Astrocytes to Treat Multiple Sclerosis

Award Number: R01NS088137
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2014
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Targeting TGFb/IFNy-IRF8 Signaling to Modulate Monocytes and their Crosstalk with Microglia and Astrocytes to Treat Multiple Sclerosis - PROJECT SUMMARY Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). Despite advances in our understanding of MS pathophysiology, there are minimal disease-modifying treatments or preventions for innate-mediated, secondary-progressive forms of MS. Our long-term goal is to define the role of interactions between microglia and recruited monocytes at different stages of MS and determine which phenotypes and functions lead to progressive forms of MS. We made the following preliminary observations: 1) ITGB8-TGFb signaling regulates astrocyte-microglia crosstalk in neurodegeneration with Irf8 regulation; 2) Deleting microglial Irf8 enhances an MGnD phenotype associated with suppression of TGFb-IFNg upstream regulators; 3) monocytes from SPMS patients have a suppression in IRF8 and induction of neurodegenerative signature; and 4) TGFb-IFNg stimulation restores homeostatic signature in monocytes/macrophages. Based on these findings, we hypothesize that TGFb/IFNg-IRF8 axis induces beneficial microglia and monocyte phenotypes in MS. Here, we propose a multi-disciplinary approach that integrates novel tools, experimental paradigms and our complementary expertise on monocytes, microglia, astrocytes and MS and its pre-clinical models. We will address our hypothesis in the following aims: Aim 1: Investigate the role of TGFb/IFNg-IRF8 signaling in monocytes on the regulation of microglia in MS models. We will 1) Determine the effect of TGFb/IFNg-mediated IRF8 signaling in monocytes on the regulation of microglial phenotypes in EAE and 2) Determine the role of IRF8 in monocytes in the regulation of ITGB8-mediated astrocyte-microglia crosstalk, and 3) Evaluate the effects of monocytes on microglia-astrocytes crosstalk in situ by MERFISH analysis. Aim 2: Modulate microglia-astrocyte crosstalk via IRF8-ITGB8 signaling in MS models. Irf8 deletion polarizes microglia to a neurodegenerative phenotype, activating astrocytes via a Lgals3-ITGB8 negative feedback regulation. To elucidate this crosstalk, we will 1) Conditionally remove IRF8 in pan-microglia during the demyelination stage; 2) Perform fate-map and conditional deletion of Irf8 in MGnD microglia; and 3) Genetically and pharmacologically inhibit ITGB8 in astrocytes. Aim 3: Establish whether modulation of TGFb/IFNg-IRF8 signaling in human monocytes and microglia can serve as a novel therapeutic modality in MS. We will 1) Determine whether restoration of IRF8 signaling via TGFb/IFNg signaling in SPMS monocytes polarizes homeostatic microglia; 2) Elucidate how IRF8 modulation in monocytes affects microglia-astrocyte crosstalk, and whether this effect is ITGB8-dependent; 3) Investigate the role of IRF8 in human microglia and their contribution to demyelination in humanized cuprizone model. IN SUMMARY, this application will elucidate the previously unrecognized role of TGFb/IFNg-IRF8 axis in monocytes-astrocyte-microglia crosstalk in multiple sclerosis progression.


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: 2026 ( Subtotal = $644,207 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	4/13/2026	NON-COMPETING CONTINUATION	$644,207
														Subtotal = $644,207

Issue Date FY: 2025 ( Subtotal = $644,207 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	6/13/2025	COMPETING CONTINUATION	$644,207
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	10/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $644,207

Issue Date FY: 2023 ( Subtotal = $392,305 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/20/2023	NON-COMPETING CONTINUATION	$392,305
														Subtotal = $392,305

Issue Date FY: 2022 ( Subtotal = $374,973 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/30/2022	NON-COMPETING CONTINUATION	$374,973
														Subtotal = $374,973

Issue Date FY: 2021 ( Subtotal = $374,973 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	6/10/2021	NON-COMPETING CONTINUATION	$374,973
														Subtotal = $374,973

Issue Date FY: 2020 ( Subtotal = $374,973 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	7/13/2020	NON-COMPETING CONTINUATION	$374,973
2020	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/27/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $374,973

Issue Date FY: 2019 ( Subtotal = $374,973 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	9/11/2019	COMPETING CONTINUATION	$374,973
														Subtotal = $374,973

Issue Date FY: 2018 ( Subtotal = $342,657 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/23/2018	NON-COMPETING CONTINUATION	$342,657
														Subtotal = $342,657

Issue Date FY: 2017 ( Subtotal = $341,258 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/26/2017	NON-COMPETING CONTINUATION	$341,258
														Subtotal = $341,258

Issue Date FY: 2016 ( Subtotal = $354,375 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/19/2016	NON-COMPETING CONTINUATION	$354,375
														Subtotal = $354,375

Issue Date FY: 2015 ( Subtotal = $344,068 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/14/2015	NON-COMPETING CONTINUATION	$344,068
														Subtotal = $344,068

Issue Date FY: 2014 ( Subtotal = $343,326 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/19/2014	NEW	$343,326
														Subtotal = $343,326

Grand Total All Awards = $4,906,295

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Targeting TGFb/IFNy-IRF8 Signaling to Modulate Monocytes and their Crosstalk with Microglia and Astrocytes to Treat Multiple Sclerosis

Award Number: R01NS088137

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2014

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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