SLIT3/ROBO1 signaling in jaw bone development

Active Project Grant Awarded Last action

Award ID
F31DE036429
Recipient
Awarding agency
Obligated
$37,163

Award facts

Assistance listing
93.121 Oral Diseases and Disorders Research
Completion date 0% complete
Place of performance
Kansas City, MO 64108, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Micrognathia, a severely short lower jaw, is a craniofacial anomaly that impedes breathing and eating in affected infants. Even with airway intervention at birth, mortality on the first day of life for infants with micrognathia can reach 55%. For surviving infants, current treatments rely on multiple invasive and costly surgeries spanning infancy to adulthood. There is a critical unmet need for non-surgical approaches capable of safely promoting mandibular growth before birth. Such interventions require a precise understanding of the cellular and molecular mechanisms that govern lower jaw elongation during embryonic development. A comparative avian model provides a powerful system for uncovering these mechanisms. Quail and duck embryos both possess bony jaws like mammals, but quail have a short jaw while duck have a long jaw. Previous work has shown that species- specific differences in the balance of bone formation and bone resorption contribute substantially to these divergent jaw outcomes: long-jawed duck form more bone and resorb less bone than short-jawed quail during the same developmental window. Experimental manipulation of these processes alters jaw length accordingly. However, the molecular signals responsible for these distinct cellular behaviors remain incompletely defined. Recent transcriptomic comparisons identified enriched expression of SLIT3/ROBO1 signaling in developing duck jaw bone compared to quail. In long bone osteoblast lineage cells, SLIT3/ROBO1 activation enhances β-catenin- dependent transcription of pro-osteogenic genes, increasing bone deposition. In long bone osteoclasts, SLIT3/ROBO1 signaling elevates mafb activity, which downregulates osteoclastogenic programs and reduces bone resorption. Both effects favor increased bone mass and are consistent with mechanisms known to lengthen the embryonic jaw. Preliminary in OVO delivery of recombinant SLIT3 in quail embryos supports the potential of this pathway to increase jaw length. This project tests the hypothesis that SLIT3/ROBO1 signaling drives embryonic lower jaw elongation by jointly enhancing bone formation and suppressing bone resorption. Aim 1 will define how SLIT3/ROBO1 signaling influences osteoclast-mediated bone resorption. Gain- and loss-of-function manipulations in developing quail and duck jaws will quantify resulting changes in bone resorption and mandibular length. Aim 2 will determine how SLIT3/ROBO1 signaling regulates osteoblast lineage-mediated bone deposition. Together, these studies will reveal whether SLIT3/ROBO1 signaling is necessary and sufficient to coordinate the balance of bone deposition and resorption that establishes jaw length. By elucidating a novel regulator of late embryonic craniofacial bone growth, this work will advance fundamental understanding of craniofacial development and inform future non-surgical therapies for micrognathia. Further, this fellowship will provide the candidate with the necessary domain knowledge, technical skills, and professional competencies to thrive as an independent and productive research leader in craniofacial bone biology.

Quick answers

Who received award F31DE036429?

F31DE036429 was awarded to The Curators Of The University Of Missouri by National Institute of Dental and Craniofacial Research (National Institutes of Health) on March 1, 2027.

How much is award F31DE036429 worth?

$37,163 has been obligated on F31DE036429.

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