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EphB/EphrinB signaling in Systemic Sclerosis

Award Number: R01AR076489
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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EphB/EphrinB signaling in Systemic Sclerosis - Project Summary This proposal identifies the EphB2 receptor tyrosine kinase and its cognate EphrinB ligands as potential therapeutic targets to prevent vascular damage and fibrosis associated with systemic sclerosis (SSc, also known as scleroderma). A hallmark of SSc is the progressive and overwhelming deposition of extracellular matrix components, especially collagen, to cause the skin to become fibrotic and lose its elasticity. This process is thought to be driven by the recruitment of immune cells to sites of tissue damage, providing an inflammatory microenvironment to enhance fibroblast-to-myofibroblast transitions that in SSc patients leads to pathological expansion of pro-fibrotic cells and massive upregulated expression of collagen and other genes involved in fibrosis. As the biochemical pathways that control these events remain incompletely described, we focused our attention on potential membrane-associated molecules that may help interpret extracellular signals and aid the conversion of dermal fibroblasts into fibrogenic myofibroblasts, and identified the EphB2 receptor interacting with its EphrinB ligands as possible important components. Emerging data support the involvement of EphB-EphrinB in fibrosis of multiple organs, including our previous work, however little is known about the potential role of these highly conserved signaling molecules in the pathogenesis of SSc. Using human skin biopsies and mouse models of skin fibrosis, we will test the hypothesis that upon chronic, immune-mediated skin injury, EphB2 expression becomes strongly upregulated and the enhanced signaling pathways activated by this molecule are critical for the transdifferentiation of quiescent dermal fibroblasts into fibrogenic myofibroblasts to help bring about skin fibrosis. Our general idea is that when bound to EphrinB ligands expressed on various cells of the injured skin microenvironment (including endothelial cells), activated EphB2- expressing fibroblasts will initiate a differentiation process leading to their transformation into pro-fibrotic myofibroblasts. In support of this, preliminary data is provided that shows EphB2 expression is highly upregulated in human skin from SSc patients and in normal human dermal fibroblasts exposed to the pro- fibrotic inflammatory cytokine TGF-β1, and that skin fibrosis can be modulated by disrupting EphB2 either through genetic mutation or novel pharmacological approaches. The preliminary data has guided the formulation of three Specific Aims that will further test our ideas. Aim 1 will determine whether activation of EphB2 forward signalling is required for the progression of skin fibrogenesis. Aim 2 will test the hypothesis that EphB2-EphrinB interactions and signaling contributes to vascular damage and defective angiogenesis in SSc. Finally, Aim 3 will determine whether therapeutic targeting of these molecules will mitigate skin fibrosis. The proposed research is highly significant and innovative as it will reveal a key molecular mechanism that drives excessive fibrosis in SSc, and will also provide important early data on how novel small molecules that target EphB2-EphrinB interactions and signaling could be employed as future therapies to treat SSc.


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 = $609,418 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/17/2025	NON-COMPETING CONTINUATION	-$321,717
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/22/2024	NON-COMPETING CONTINUATION	$335,251
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	6	8/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$274,167
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	8/6/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	005	5	9/25/2025	NON-COMPETING CONTINUATION	$321,717
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	004	5	8/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $609,418

Issue Date FY: 2023 ( Subtotal = $345,620 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	8/3/2023	NON-COMPETING CONTINUATION	$345,620
														Subtotal = $345,620

Issue Date FY: 2022 ( Subtotal = $342,164 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/5/2022	NON-COMPETING CONTINUATION	$342,164
														Subtotal = $342,164

Issue Date FY: 2021 ( Subtotal = $335,251 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/26/2021	NON-COMPETING CONTINUATION	$335,251
														Subtotal = $335,251

Issue Date FY: 2020 ( Subtotal = $358,305 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/9/2020	NEW	$358,305
														Subtotal = $358,305

Grand Total All Awards = $1,990,758

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EphB/EphrinB signaling in Systemic Sclerosis

Award Number: R01AR076489

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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