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Small molecule microenvironment design for craniofacial bone regeneration

颅面骨再生的小分子微环境设计

基本信息

批准号：
10000905
负责人：
Xianghong Luan
金额：
$ 36.16万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000905
关键词：
Affect Alveolar Bone Loss Animals Biological Bone Growth Bone Matrix Bone Regeneration Bone Tissue Cell Differentiation process Cell Proliferation Cephalic Clinical Collagen Defect Dentists Deposition Disease Engineering Environment Epigenetic Process Excision Exposure to Extracellular Matrix Extracellular Matrix Proteins Face Fibronectins Future Gelatin Gene Expression Profiling Genetic Histology Histone-Lysine N-Methyltransferase Instruction Length Malignant Neoplasms Mechanics Mediating Mediator of activation protein Mesenchymal Methylation Molecular Mus Nanosphere Natural regeneration Nuclear Operative Surgical Procedures Osteoblasts Osteocalcin Osteogenesis Patient Care Patients Periodontal Diseases Periodontal Ligament Periodontitis Physiologic Ossification Population Process Proteins Proteoglycan Regimen Shotguns Signal Transduction Testing Therapeutic Tissue Engineering Tissues Tooth root structure Transcriptional Activation Trauma WNT Signaling Pathway Weight-Bearing state alveolar bone base bone bone cell bone loss controlled release craniofacial craniofacial bone cranium crosslink design extracellular in vitro Model in vivo inhibitor/antagonist intramembranous bone intramembranous bone formation long bone mechanical properties microCT mineralization nanoparticle novel progenitor scaffold small molecule small molecule inhibitor stem cell proliferation therapy outcome

项目摘要

Over 30,000 people per year undergo craniofacial resective surgery and approximately 15% of the US population suffers from periodontal disease severe enough to warrant surgery (Marolt 2015). Currently, craniofacial and periodontal bone tissue engineering faces unique challenges due to the exposure of cranial and periodontal bones to continuous and varying loads (Rah 2000). The effect of continuous loads onto the engineered construct necessitates a gradual augmentation of an engineered regenerate rather than the en bloc insertion of a mechanically inert replacement tissue. In contrast to long bones, which are formed through endochondral ossification, cranial vault and periodontal bones are characterized by their unique mode of intramembranous ossification, which is accomplished through the stepwise mineralization of a specialized extracellular protein matrix rich in collagen and proteoglycans. When cranial and/or periodontal bones are lost due to trauma or disease, this loss not only affects osteoblasts, progenitors, and other bone cells, but also the unique extracellular bone matrix that maintains the instructive signaling environment for continuous bone regeneration and replacement. In the present application we have focused on a recently described small molecule mediator, the SETD7 histone lysine methyltransferase inhibitor PFI-2 that in our preliminary studies has induced osteoblasts to secrete a typical bone-like extracellular matrix enriched in collagen, fibronectin and osteocalcin. In animal studies, PFI-2 has demonstrated extraordinary potential to induce bone regeneration, including alveolar bone regeneration over half of a tooth root’s length and more than 50% new bone coverage of critical size cranial defects. Providing a possible mechanism for these exciting new findings, we have demonstrated that PFI-2 inhibited SETD7 mediated -catenin methylation, resulting in nuclear -catenin translocation and bone matrix protein transcription activation in addition to the stimulation of other processes related to new bone formation, such as cell proliferation and differentiation. In the present application, we seek to exploit PFI-2’s potential for cranial and periodontal bone regeneration, define the mechanism(s) by which PFI-2 triggers new bone extracellular matrix deposition, and engineer scaffolds of sufficient stability to provide a template for PFI-2 nanosphere controlled release toward future applications in clinical use and patient care.

每年有超过3万人接受颅面切除手术