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Keratinocyte Integrin Crosstalk During Wound Healing.

Award Number: R01AR063778
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: 02/20/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Keratinocyte Integrin Crosstalk During Wound Healing. - PROJECT SUMMARY Epidermal keratinocytes are vital to normal wound healing by restoring the epidermal barrier and secreting paracrine factors that govern diverse processes including wound angiogenesis and myofibroblast function. In pathogenic settings, impaired epidermal function results in chronically insufficient (e.g., diabetic ulcers) or over- exuberant healing (e.g., hypertrophic scars). Our long-term goal is to develop therapeutic paradigms through which integrins can be manipulated to modulate pathogenic keratinocyte function. While it is well established that integrins regulate proliferation, migration and growth factor signaling, their roles in orchestrating wound keratinocyte functions remain enigmatic. Moreover, while normal and wound keratinocytes express integrin 91, in vivo, upon explanation integrin 91 is lost, confounding observations made in previous studies, in vitro. Using genetically defined, virally transduced keratinocytes that express integrins 31 and/or 91 in different combinations, we discovered in the last project period that 91 exerts a cross-suppressive effect on wound cell function and gene expression that is governed by 31, including paracrine signals that promote endothelial cell function and autocrine signals that regulate basement membrane assembly. Using genetically defined mice that we have derived expressing different combinations of 31 and/or 91 in the epidermis, we also found that deletion of 91 from epidermis promoted wound angiogenesis and enhanced laminin 2 processing in the regenerating, epidermal basement membrane after injury. Based on our recently published studies and new foundation data, we now hypothesize that 91 cross-suppresses 31-dependent keratinocyte functions through inhibition of a novel 31-FAK-YAP/TAZ signaling axis. We further hypothesize that this signaling axis controls a gene expression program that promotes keratinocyte wound functions, including paracrine stimulation of endothelial cells and fibroblasts and autocrine regulation of basement membrane assembly. This hypothesis will be tested in three Aims using a combination of co-culture models, qPCR arrays, proteomics, PAC-seq mRNA analysis, cell biology, and defined genetic mouse models. At the end of this project period, we will have built on the foundation developed in the first project period to elucidate the complex signaling network downstream of integrin signaling in keratinocytes that governs paracrine and autocrine signaling in normal wounds. We will also have determined how these integrin signaling pathways are altered in epidermal tumors in which angiogenesis and other wound processes persist. In doing so, we will have developed the basis for novel integrin targeting therapeutics to modulate keratinocyte function and wound outcome.


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 = $0 )
2025	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	7/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $466,249 )
2023	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	3/13/2023	NON-COMPETING CONTINUATION	$466,249
														Subtotal = $466,249

Issue Date FY: 2022 ( Subtotal = $461,586 )
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	6/9/2022	NON-COMPETING CONTINUATION	$41,961
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	3/21/2022	NON-COMPETING CONTINUATION	$419,625
														Subtotal = $461,586

Issue Date FY: 2021 ( Subtotal = $452,260 )
2021	2021	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	8	9/2/2021	NON-COMPETING CONTINUATION	$0
2021	2021	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	6/22/2021	NON-COMPETING CONTINUATION	$32,635
2021	2021	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	3/5/2021	NON-COMPETING CONTINUATION	$419,625
														Subtotal = $452,260

Issue Date FY: 2020 ( Subtotal = $466,249 )
2020	2020	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	5/1/2020	NON-COMPETING CONTINUATION	$466,249
														Subtotal = $466,249

Issue Date FY: 2019 ( Subtotal = $466,249 )
2019	2019	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	4/1/2019	COMPETING CONTINUATION	$466,249
2019	2017	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/6/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $466,249

Issue Date FY: 2017 ( Subtotal = $335,750 )
2017	2017	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	12/20/2016	NON-COMPETING CONTINUATION	$302,175
2017	2017	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/14/2017	NON-COMPETING CONTINUATION	$33,575
														Subtotal = $335,750

Issue Date FY: 2016 ( Subtotal = $335,750 )
2016	2016	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	11/19/2015	EXTENSION WITH OR WITHOUT FUNDS	$302,175
2016	2016	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	1/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$33,575
														Subtotal = $335,750

Issue Date FY: 2015 ( Subtotal = $335,750 )
2015	2015	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/22/2014	NON-COMPETING CONTINUATION	$302,175
2015	2015	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	12/23/2014	NON-COMPETING CONTINUATION	$33,575
														Subtotal = $335,750

Issue Date FY: 2014 ( Subtotal = $335,750 )
2014	2014	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/13/2013	NON-COMPETING CONTINUATION	$302,175
2014	2014	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/21/2014	NON-COMPETING CONTINUATION	$33,575
														Subtotal = $335,750

Issue Date FY: 2013 ( Subtotal = $327,125 )
2013	2013	ALBANY MEDICAL COLLEGE OF UNION UNIVERSITY	47 NEW SCOTLAND AVENUE	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	2/19/2013	NEW	$327,125
														Subtotal = $327,125

Grand Total All Awards = $3,982,718

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Keratinocyte Integrin Crosstalk During Wound Healing.

Award Number: R01AR063778

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: 02/20/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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