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Roles of epidermal integrin α3β1 in age-dependent changes during cutaneous wound healing

Award Number: R21AR083049
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: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Roles of epidermal integrin α3β1 in age-dependent changes during cutaneous wound healing - Project Summary Even without comorbidities associated with aging, wound healing in healthy elderly people (>65) is delayed, posing a high risk of infection. However, mechanisms for the age-related decline in wound healing are largely unknown. Integrin adhesion receptors on epidermal keratinocytes bind to extracellular matrix (ECM) and have critical roles in controlling the wound microenvironment and critical parameters of wound healing. Age-dependent changes in adhesion receptors may contribute to reduced wound healing in aged skin, but these have not been explored. This is an important knowledge gap, as integrins are cell surface receptors that can be readily targetable therapeutically. Integrin α3β1 is an excellent candidate for mediating epidermal wound functions that diminish with age. Indeed, our preliminary data show that α3β1 expression decreases in aging murine skin. Furthermore, our new genetic model of inducible, epidermis-specific α3KO (iα3eKO) has begun to elucidate α3β1-dependent wound functions in adult skin, free from compensation and/or basement membrane defects caused by embryonic and sustained deletion of epidermal α3β1 in the widely used constitutive α3KO mice. Our preliminary data indicate that acute loss of α3β1 in epidermis of young adult mice (1) slows wound reepithelialization and (2) impairs epidermal factors that mediate immune cell infiltration. Indeed, reepithelialization and immune cell infiltration are compromised in aging skin of humans and rodents, and contribute to impaired wound healing in the elderly. The proposed work will use an aging model in combination with our iα3eKO model to test our hypothesis that α3β1 in epidermis promotes wound healing by regulating two distinct processes: (1) epidermal migration over the provisional wound ECM, and (2) induction of epidermal factors that mediate immune cell infiltration, and that these α3β1-dependent functions are diminished during intrinsic (chronological) aging, impeding the ability to heal wounds. We propose two Specific Aims to test our hypothesis and answer the question: Does waning epidermal integrin α3β1 function in aging skin contribute to wound healing deficiencies in the elderly? We will determine, in vivo and in vitro, the ability of young, middle, and aged keratinocytes which express or lack α3β1 to (Aim 1) proliferate and migrate during re-epithelialization, and to (Aim 2) secrete soluble immune cell-stimulating factors that promote immune cell recruitment during wound healing. Aim 2 is a particularly innovative aspect, as it extends our studies beyond traditional roles for integrins in adhesion/motility to further explore keratinocyte-driven paracrine crosstalk. This work will enhance understanding of how age-related changes in the functions of epidermal integrins contribute to reduced wound healing.


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 = $174,988 )
2025	2025	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/14/2025	NON-COMPETING CONTINUATION	$174,988
														Subtotal = $174,988

Issue Date FY: 2024 ( Subtotal = $216,205 )
2024	2024	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/7/2024	NEW	$216,205
														Subtotal = $216,205

Grand Total All Awards = $391,193

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Roles of epidermal integrin α3β1 in age-dependent changes during cutaneous wound healing

Award Number: R21AR083049

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: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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