Deciphering and manipulating the dynamic signaling and transcriptional programs of appendage regeneration

The National Institute of Child Health and Human Development awarded The Morgridge Institute For Research, Inc., $131,832 on August 21, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to support research on appendage regeneration signaling and transcriptional programs.

The award funds investigation into how signaling dynamics, transcriptional output, and physiological cues control regenerative growth in zebrafish dermal appendages, using live imaging, optogenetics, and mathematical modeling to examine how osteoblasts interpret dynamic signals to regenerate tissue. The research quantifies ERK wave dynamics across scale regenerates of variable geometries, develops predictive models linking wave parameters to regenerative outcomes, and employs in vivo optogenetic tools to test model predictions. The work also identifies gene regulatory mechanisms governing tissue-scale regeneration and physiological integration.

Performance occurs in Madison, Wisconsin, with a period of performance ending July 31, 2028. The assistance type is a Project Grant.

Abstract

The ability to regenerate complex tissues with correct size, and shape remains a central question in regenerative biology. While mammals can regenerate bony structures in limited contexts such as digit tips, zebrafish restore dermal appendages like scales and fins with striking precision-offering externally accessible tissues that regenerate within days to weeks and serve as exceptional models for visualizing regenerative events. While these models have led to tremendous gains in knowledge of core signaling pathways required for regeneration, we still have an incomplete understanding of how spatiotemporal patterning of signaling dynamics, transcriptional output, and physiological cues converge to control regenerative growth. A major barrier to this has been the challenge of documenting such dynamic events in vivo at single-cell resolution, and of manipulating them with high spatiotemporal resolution. This proposal uses an exciting multidisciplinary approach-combining live imaging, optogenetics, and mathematical modeling-to dissect how osteoblasts within these dermal appendages interpret dynamic signals to regenerate tissue. Recent work showed that ERK activity, during scale and FIN regeneration, is spatially patterned as traveling waves or decaying gradients, suggesting that tissue-scale signaling dynamics can encode temporal and positional information. However, how the biophysical parameters of these signals are modulated to accurately regenerate tissues, and how they integrate with physiological states like ION flux and membrane potential remains unknown. In aim 1, i will quantify ERK wave dynamics across dermal scale regenerates of variable geometries and develop predictive models linking wave parameters to regenerative outcomes and use in vivo optogenetic tools to test model predictions. In aim 2, i will identify the gene regulatory mechanisms that prime osteoblasts to respond to signaling waves and examine how signaling wave patterns are decoded into transcriptional programs that affect bone growth. Lastly, in aim 3, i will quantitatively map and manipulate bioelectric cues to uncover their role in osteoblast behavior and regenerative patterning in scales and fins. The research outlined here will form the intellectual basis of my own independent research program. The project is supported by an interdisciplinary training plan with mentorship from DR. Kenneth poss, a leader in vertebrate regeneration and zebrafish genetics, and DR. Stefano DI talia, an expert in quantitative imaging and developmental modeling. Their long-standing collaboration offers a unique dual- mentorship model across institutions, combining strength in in vivo regeneration biology with quantitative systems-level analysis. I will receive hands-on training in optogenetic tool development, quantitative imaging, and theoretical modeling, with guidance from an exceptional advisory committee spanning regeneration biology, biophysics, bioelectricity, and in vivo imaging. Together, this work will uncover principles by which dynamic signals are interpreted during vertebrate appendage regeneration and lay the foundation for an independent future research program focused on decoding spatially patterned cues that govern tissue growth and repair.