Tuesday, November 4, 2025 11/4/2025

DISARMing the immunological barriers to regeneration in mammals

Award Number: R01HD110440
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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DISARMing the immunological barriers to regeneration in mammals - PROJECT SUMMARY/ABSTRACT The long-term goal of this work is to facilitate the faithful regeneration of damaged human tissues. Regeneration in adult mammals is extremely limited; damaged tissue in most major organs fails to regenerate, and instead undergoes scar-based repair. The lack of adult regenerative capacity is an enormous burden on the healthcare system and society as a whole. Although both human and mouse digit tips can undergo a true regenerative response, this regeneration is positionally restricted to the terminal distal phalanx bone. Importantly, amputations with an axis point below the terminal distal phalanx bone or too close to the nail bed result in regeneration failure. Notably, salamander limbs have an anatomy similar to that of human limbs, but uniquely regenerate after amputation from any position throughout adult life. The biological mechanisms limiting regeneration in adult mammals is poorly understood. Although the immune system is a powerful regulator of wound repair, the exact role of immune-cell networks as a determinant of regenerative success has been grossly understudied. In our regeneration studies, including those proposed here, we use the mouse digit-tip model, examining regeneration following tissue removal at different digit locations. This is a powerful model, as regeneration can be measured non-invasively with high-resolution micro-computed tomography 3D-imaging (bone/soft tissue volume), and analyzed comprehensively using histology and molecular analysis. We identified several lymphoid immune-cell types that inhibit mouse digit-tip regeneration via cytotoxic activity against progenitor cells and showed that T- regulatory cells (Tregs) play a critical role in protecting progenitors from these cells. We also found that in mice lacking lymphoid immunity, novel regeneration is induced, providing new models to identify pro-regenerative cells and molecular pathways that can be exploited therapeutically. Importantly, we also identified several lymphoid-cell types that support regeneration, suggesting the potential to therapeutically enhance human repair through targeted immunomodulation. This project aims to identify and characterize the mechanisms by which lymphoid cells regulate adult regeneration. Specifically, we will: Aim 1: Dissect and characterize lymphoid-cell mechanisms inhibiting regeneration. We will use a range of mouse strains with mutations in cytotoxic function in ex vivo and in vivo analyses. Aim 2: Define mechanisms of pro-regenerative Treg suppression of lymphoid-cell cytotoxicity using Treg-specific deletion of functional genes in vivo. Aim 3: Test the hypothesis that targeted disarming of lymphoid cells could enhance regeneration in vivo. We will test tolerogenic molecules in ex vivo cytotoxicity assays and then evaluate tolerogenic antigen overexpression in vivo both direct transgenic and viral approaches and then via a modified Treg delivery strategy. This project will fuse developmental biology and immunological methods to identify the critical biological pathways and genetic modifiers required for transient immunomodulation strategies directed at inducing latent regenerative potential in adult tissues in mammals. This work will lay the groundwork for translation studies aimed at enhancing tissue repair in human patients.


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 = $485,286 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	001	3	4/11/2025	NON-COMPETING CONTINUATION	$48,528
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	000	3	1/10/2025	NON-COMPETING CONTINUATION	$436,758
														Subtotal = $485,286

Issue Date FY: 2024 ( Subtotal = $530,451 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	000	2	1/10/2024	NON-COMPETING CONTINUATION	$535,807
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	002	2	5/1/2024	NON-COMPETING CONTINUATION	$48,224
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	001	2	1/11/2024	NON-COMPETING CONTINUATION	-$53,580
														Subtotal = $530,451

Issue Date FY: 2023 ( Subtotal = $527,871 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	000	1	3/31/2023	NEW	$516,240
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Child Health and Human Development Extramural Research	001	1	9/7/2023	NEW	$11,631
														Subtotal = $527,871

Grand Total All Awards = $1,543,608

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DISARMing the immunological barriers to regeneration in mammals

Award Number: R01HD110440

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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