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Investigating the principles of physiological and pathological vascular remodeling via 4D imaging of live mouse skin

Award Number: K99AR079555
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Investigating the principles of physiological and pathological vascular remodeling via 4D imaging of live mouse skin - PROJECT SUMMARY The cutaneous vasculature is a crucial yet understudied component of the skin, responsible for essential functions such as tissue oxygenation, exchange of nutrients and soluble factors, and temperature control. While we have a significant understanding of vascular abnormalities present in various skin pathologies, we lack an understanding of both physiological remodeling and homeostatic mechanisms sustaining lifelong function. Specifically, we lack the resolution of the coordinated cellular behaviors that drive developmental vascular remodeling, as well as those that underlie vascular regeneration in the face of injury, particularly in the context of hemodynamic status. I hypothesize that network-wide coordination of EC behaviors in relation to hemodynamic changes regulates developmental and regenerative remodeling programs of the skin vasculature. To test this hypothesis, I have established an intravital imaging technique that allows for the longitudinal tracking and manipulation of the endothelial cells (ECs) that constitute the lining of all blood vessels in the skin of a live mouse. In Aim 1, I will investigate the neonatal vessel remodeling program and underlying EC behaviors that orchestrate the establishment of skin vascular network architecture and blood flow efficiency. Following establishment of adult vascular homeostasis, I will probe the cellular mechanisms that regulate the maintenance of adult vessel integrity via a targeted laser ablation approach, modeling the discrete membrane damage inflicted upon the endothelium due to shear and contractile forces. My preliminary data shows that EC migration within existing vessel structures is a critical EC behavior that underlies network-wide vessel regression during neonatal remodeling, as well as the reparative response of adult ECs to local damage. In Aim 2, I will transition my studies towards the understanding of the skin vasculature in the context of pathological states. Firstly, I will investigate the wound vascularization mechanisms of neonatal versus adult skin, and delineate the differential remodeling properties that enable the enhanced wound revascularization in neonatal skin that we have observed in preliminary experiments. Second, I will determine how coordination of flow-dependent EC rearrangement impacts the ability of adult wounds to revascularize via a genetic mutant model that uncouples the ability of ECs to polarize with respect to blood flow direction. To achieve these aims, I will use an integrated approach of cutting-edge imaging technology, transcriptomics, and genetic mouse models. This research is significant because we expect to uncover global cellular and molecular mechanisms that coordinate vascular development, homeostasis, and injury repair. My findings will likely drive innovation in related fields, given the ubiquity and crucial roles of the vasculature in all organs.


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 = -$35,445 )
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	8/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/10/2025	NON-COMPETING CONTINUATION	-$35,445
														Subtotal = -$35,445

Issue Date FY: 2024 ( Subtotal = $106,035 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/28/2024	NON-COMPETING CONTINUATION	$106,035
														Subtotal = $106,035

Issue Date FY: 2023 ( Subtotal = $106,035 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/31/2023	NEW	$106,035
														Subtotal = $106,035

Grand Total All Awards = $176,625

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Investigating the principles of physiological and pathological vascular remodeling via 4D imaging of live mouse skin

Award Number: K99AR079555

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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