Deciphering the role of neuropeptides in appendage regeneration

The National Institute of Child Health and Human Development awarded The Marine Biological Laboratory $431,112 on September 1, 2026, under the Child Health and Human Development Extramular Research program (CFDA 93.865) to investigate the role of neuropeptides in appendage regeneration.

The research seeks to understand why salamanders and axolotls regenerate lost limbs, jaws, tails, and other tissues while humans retain only limited regenerative capacity. The work addresses therapeutic applications ranging from scarless wound healing to treatments for degenerative diseases and potential human limb regeneration. The project focuses on long-distance signaling mechanisms—specifically neuropeptide-mediated signals traveling from the spinal cord and brain to the injury site—that instruct cells to migrate, divide, and form the blastema that drives regenerative growth.

The award is a Project Grant, the assistance type category for NIH peer-reviewed extramural research. Performance occurs at The Marine Biological Laboratory in Woods Hole, Falmouth, Massachusetts, with a period of performance from September 1, 2026, through August 31, 2028. The Marine Biological Laboratory is a nonprofit research institution that delivers fundamental biological research, advanced research training, and specialized laboratory facilities including live research organisms and microscopy infrastructure to federal science agencies.

Abstract

Why can a salamander regenerate a lost arm, jaw, tail, iris, and even part of its heart, but a man cannot regrow anything more than the tiniest tip of his finger or a portion of the liver? This question has fascinated scientists since the 1780S when the impressive regenerative powers of the salamander were first reported. In humans, injuries often cannot be remedied, leading to persistent debilitation and mortality. As the number of patients suffering from incomplete healing and lack of regenerative growth is greater than 1.5 million in the past year alone, the burden on the health system is significant. For example there are approximately 185,000 limb amputations per year in the US alone - humans cannot regenerate limbs; they may retain evolutionarily conserved ability for regenerative growth but lack the ability/signals to appropriately initiate these programs while trying to understand salamander regeneration has challenged researchers for centuries, the potential therapeutic applications of induced, controlled human tissue regeneration are immense, ranging from enhanced or "scarless" wound healing to superior treatments for tissue degenerative diseases (i.e., parkinson's disease, degenerative arthritis), to regenerating a hand or arm. Limb regeneration in axolotls has been studied for a long-time, and we know a lot about the locally induced factors needed to instruct cells adjacent to the injury site to migrate, start dividing, and form a blastema. Over the past two decades, research on the axolotl has primarily focused on how cells immediately adjacent to the injury site facilitate functional limb regeneration. Motor neurons and sensory neurons innervate the limb from the brachial plexus, which originate from the spinal cord. The neurons in the spinal cord connect via long tract axons to the brain. This creates a long-distance highway on which signals must be sent from the injury site to the brain and vice versa. Importantly, such long-range projection neurons are critical for regulating voluntary movement and are therefore necessary for functional limb regeneration. Thus, if we are to fully elucidate how regeneration-competent species can successfully regenerate in response to an injury, we must also investigate what signals are being trafficked from the brain to the injury site to instruct damaged cells to regenerate. We hypothesize that activation of dperk signaling in these excitatory glutamatergic neurons is necessary to drive a response to a distant injury and to instruct cells to execute a pro-regenerative response. A major knowledge GAP exists in understanding how the brain responds to injury and communicates to the distant injury site. In aim 1, we will identify the neuropeptides that regulate key aspects of axolotl limb regeneration. In aim 2, we will decipher key circuitry that promotes digit tip regeneration in the mouse and identify those that are absent or prevent P2 digit tip regeneration in the mouse. Our overarching goal is to advance the field of regenerative medicine by defining the roles of key neuropeptides in promoting limb regeneration.