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Blastema-independent Mechanism for Regeneration in Salamanders

Award Number: R21AR078939
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: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Blastema-independent Mechanism for Regeneration in Salamanders - PROJECT SUMMARY While human and other mammals are limited in their abilities to regenerate, the salamanders, including Ambystoma mexicanum (axolotl) are highly regenerative and have provided numerous insights into the mechanisms of organ repair. Upon injury, axolotls generate “blastema” tissue at the wound site, which harbors multipotent progenitors that engage in regenerative healing, contributing to multiple newly forming cell types. The inability of mammals to form multipotent blastema cells is commonly thought to be the key barrier to true regenerative wound healing. Axolotls can also regenerate skin, which normally consists of an epidermis, a two- layer dermis as well as many secretory glands. Contrary to the prevailing notion that complete tissue regeneration requires blastema, we now show that the axolotl skin regenerates without a blastema and that, in fact, blastema formation represses glandular skin regeneration. This application will focus on defining a novel cellular and signaling mechanism of blastema-independent skin regeneration in salamanders. To achieve this goal, this project will leverage the analytical strengths of the so-called Accessory Limb Model (ALM) – a highly tractable wound model system in axolotls that can be experimentally directed to either: (i) rapidly regenerate gland-containing skin without a blastema, or (ii) form a blastema when presented with a deviated nerve and display prominently delayed skin regeneration. Using a combination of live axolotl imaging, lineage tracing, single-cell RNA-seq, functional protein delivery, and gene perturbation assays in the ALM model, in our first aim we will establish if amphibian skin gland regeneration critically depends on epidermal-dermal interactions and if these interactions are prevented in blastema-forming wounds due to the immaturity of their fibroblasts. The second aim is to uncover new signaling and epigenetic mechanisms of gland neogenesis in regenerating skin. In particular, we will establish the activating role of the Bone Morphogenic Protein ligand BMP7 and the counterbalancing role of its antagonist GREMLIN and the activating role of Class II histone deacetylase HDAC10 – top-listed differentially expressed genes in our RNA- seq studies – on gland regeneration and skin fibroblast lineage maturation. The study premise is strong, based on substantial preliminary data. The proposed studies are significant because they will introduce amphibian skin as a novel model for studying mechanisms of skin regeneration and will advance knowledge on skin cell types in amphibians. The proposed studies are innovative because they will establish a novel paradigm of blastema-independent regeneration and will identify new skin regeneration-inducing epigenetic and signaling factors. Ultimately, we want to be able to translate new knowledge learned from this amphibian model system of blastema-independent skin regeneration to better understand skin regeneration mechanisms in mammals, whose tissues typically heal without a blastema.


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	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $172,700 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/22/2022	NON-COMPETING CONTINUATION	$155,430
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/12/2023	NON-COMPETING CONTINUATION	$17,270
														Subtotal = $172,700

Issue Date FY: 2022 ( Subtotal = $207,240 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/21/2022	NEW	$207,240
														Subtotal = $207,240

Grand Total All Awards = $379,940

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Blastema-independent Mechanism for Regeneration in Salamanders

Award Number: R21AR078939

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: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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