Small molecule microenvironment design for craniofacial bone regeneration

颅面骨再生的小分子微环境设计

• 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
• 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

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30，000人接受颅面切除手术， 15%的美国人口患有牙周病严重到足以保证手术 （Marolt 2015）。目前，颅面和牙周骨组织工程面临独特的 由于颅骨和牙周骨暴露于连续和变化的环境中， 载荷（Rah 2000）。连续载荷对工程结构的影响需要 逐渐增加的工程再生，而不是整块插入一个 机械惰性替代组织。与长骨相反，长骨是通过 软骨内骨化、颅穹窿和牙周骨的特征在于其独特的 膜内骨化模式，通过逐步 富含胶原蛋白和蛋白聚糖的特化细胞外蛋白基质的矿化。 当颅骨和/或牙周骨由于创伤或疾病而丢失时，这种丢失不仅 影响成骨细胞、祖细胞和其他骨细胞，也影响独特的细胞外骨， 维持持续骨再生的指导性信号环境的基质 和替换。在本申请中，我们已经集中于最近描述的小的微电子器件。 分子介导剂，SETD 7组蛋白赖氨酸甲基转移酶抑制剂PFI-2， 初步研究已诱导成骨细胞分泌典型的骨样细胞外基质 富含胶原蛋白、纤连蛋白和骨钙素。在动物研究中，PFI-2已经证明 具有诱导骨再生的非凡潜力，包括牙槽骨再生， 牙根长度的一半和超过50%的新骨覆盖临界尺寸的颅骨 缺陷为这些令人兴奋的新发现提供了可能的机制，我们有 证明PFI-2抑制了SETD 7介导的β-连环蛋白甲基化，导致细胞核 β-连环蛋白易位和骨基质蛋白转录激活， 刺激与新骨形成相关的其他过程，如细胞增殖， 分化在本申请中，我们寻求开发PFI-2在颅和脑内的潜力。 牙周骨再生，定义PFI-2触发新骨的机制 细胞外基质沉积，并设计足够稳定支架以提供模板 对于PFI-2纳米球控制释放在临床使用和患者中的未来应用 在乎