Mechanisms of accelerated regeneration in neural crest-derived bone

About This Grant

PROJECT SUMMARY Craniofacial bones, unlike other bones in the skeleton, originate from both neural crest and mesoderm. Studies have indicated that bones derived from neural crest regenerate faster than those from mesoderm, but the mechanisms behind this remain poorly understood. We discovered a novel network of p75 neurotrophin receptor-positive (p75-NTR+) cells within the periosteum of neural crest-derived bones that are crucial for the rapid regeneration of these skeletal sites. My central hypothesis is that these cells represent a distinct subset of neural crest-derived stem cells that are developmentally programmed to accelerate craniofacial regeneration through two independent mechanisms: (1) direct osteolineage differentiation and (2) the establishment of a pro-regenerative immune niche. My long-term goal as a dentist-scientist is to identify endogenous mechanisms of accelerated skeletal regeneration and to translate these findings into novel therapeutics that can promote cranial and dentoalveolar bone regeneration. The proposed K99/R00 research and training is designed to help me to achieve this goal. The K99 mentored phase of the project will be carried out with Dr. Erica Scheller and Dr. Farshid Guilak (primary co-mentors) at Washington University in St. Louis. The goal of the K99 phase is to provide additional training and mentoring in three areas: 1) Lab Management, 2) Bioinformatics and in silico New Approach Methodologies (NAMs), and 3) Inflammation and Immunology. A strong Scientific Advisory Committee with members from Washington University in St. Louis, Johns Hopkins University, and the University of Pittsburg has been established with diverse expertise in bone biology, skeletal regeneration and imaging, immunology, and bioinformatics/NAMs to oversee a training plan that complements and expands my scientific background, preparing me for a transition to independence during the R00 phase as faculty at a research-focused institution. To further dissect the regenerative potential of the novel p75-NTR+ cells and their contribution to the acceleration of neural crest-derived bone healing, I am proposing two research aims in this application as follows: Aim 1. define the dual osteogenic and immunomodulatory roles of p75-NTR+ periosteal cells in craniofacial bone regeneration; and Aim 2. explore the targeting of p75-NTR+ cells as a therapeutic strategy to accelerate craniofacial regeneration. Overall, the proposed experiments aim to identify the intrinsic biological pathways that accelerate bone healing while considering the implications of these results for clinical management of skeletal disease. This research holds significant translational therapeutic potential for patients with skeletal defects and is expected to ultimately improve patient outcomes and quality of life.