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Composite tissue patterning in mammalian digit tip regeneration

Award Number: R01HD115260
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: 04/02/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Composite tissue patterning in mammalian digit tip regeneration - PROJECT SUMMARY The digit tips of many mammals, including humans, innately regenerate following amputation. Multi-tissue digit tip regeneration requires coordinated proliferation and interaction of many cell types in a structure termed the ‘blastema’. Significant progress has been made in defining the origin and cellular composition of the mouse digit tip blastema, but there is a gap in our understanding of how the heterogeneous blastema becomes a correctly organized and shaped composite tissue. This proposal focuses on defining the molecular mechanism(s) of patterning the regenerating mouse digit tip. In general, broad similarities between the regenerative blastema and the embryonic limb bud underlie the hypothesis that gene networks required for embryonic limb patterning are re-deployed in the regenerative blastema. While studies support this hypothesis in some non-mammalian models of limb regeneration, our data demonstrate that this is not true for dorsal- ventral patterning during mouse digit tip regeneration. This suggests that mammalian and non-mammalian limb-derived blastemas may employ different mechanisms for re-establishing limb tissue morphology. We propose that the mammalian digit tip blastema utilizes non-developmental patterning mechanisms and receives molecular patterning cues from the nail epithelium. In this proposal, we focus on the dorsal-ventral and proximal-distal anatomical axes; we aim to determine the patterning mechanism(s) in the mouse digit tip blastema and to determine how manipulation of these pathways during regeneration impacts morphology. Toward this, we will model and molecularly define proximal-distal patterning genes using computational and genetic approaches. We will also use grafting studies to determine the tissue patterning autonomy of the digit tip blastema. Finally, we will visualize putative dorsal-ventral electrochemical gradients in the blastema and perform gain and loss of function studies to manipulate these signals. Collectively, the data generated from this project will reveal patterning mechanisms for mammalian digit tip regeneration and highlight how this may be fundamentally different from non-mammalian limb regeneration models. This research will ultimately inform blastema induction efforts for mammalian full limb amputations because exogenous patterning information may need to be provided.


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: 2026 ( Subtotal = $704,713 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	3	3/19/2026	NON-COMPETING CONTINUATION	$704,713
														Subtotal = $704,713

Issue Date FY: 2025 ( Subtotal = $750,426 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	2	4/4/2025	NON-COMPETING CONTINUATION	$750,426
														Subtotal = $750,426

Issue Date FY: 2024 ( Subtotal = $771,691 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	1	4/2/2024	NEW	$771,691
														Subtotal = $771,691

Grand Total All Awards = $2,226,830

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Composite tissue patterning in mammalian digit tip regeneration

Award Number: R01HD115260

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: 04/02/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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