Small molecule microenvironment design for craniofacial bone regeneration
Small molecule microenvironment design for craniofacial bone regeneration
批准号:
10190888
负责人:
Xianghong Luan
金额:
$0.0万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-07-20 至 2023-01-31
关键词:
AffectAlveolar Bone LossAnimalsBiologicalBone GrowthBone MatrixBone RegenerationBone TissueCell Differentiation processCell ProliferationCephalicClinicalCollagenDefectDentistsDepositionDiseaseEngineeringEnvironmentEpigenetic ProcessExcisionExposure toExtracellular MatrixExtracellular Matrix ProteinsFaceFibronectinsFutureGelatinGene Expression ProfilingGeneticHistologyHistone-Lysine N-MethyltransferaseInstructionLengthMalignant NeoplasmsMechanicsMediatingMediator of activation proteinMesenchymalMethylationMolecularMusNanosphereNatural regenerationNuclearOperative Surgical ProceduresOsteoblastsOsteocalcinOsteogenesisPatient CarePatientsPeriodontal DiseasesPeriodontal LigamentPeriodontitisPhysiologic OssificationPopulationProcessProteinsProteoglycanRegimenShotgunsSignal TransductionTestingTherapeuticTissue EngineeringTissuesTooth root structureTranscriptional ActivationTraumaWNT Signaling PathwayWeight-Bearing statealveolar bonebasebonebone cellbone losscontrolled releasecraniofacialcraniofacial bonecraniumcrosslinkdesignextracellularin vitro Modelin vivoinhibitor/antagonistintramembranous boneintramembranous bone formationlong bonemechanical propertiesmicroCTmineralizationnanoparticlenovelprogenitorreplacement tissuescaffoldsmall moleculesmall molecule inhibitorstem cell proliferationtherapy outcome
中文摘要
每年有超过30,000人接受颅面切除手术,大约
15%的美国人患有牙周病,严重到需要手术
(Marolt 2015)。目前,颅面和牙周骨组织工程面临着独特的
颅骨和牙周骨暴露在连续和变化的环境中的挑战
负荷(RAH 2000)。工程结构上的连续荷载的影响需要一个
逐步增加工程再生物,而不是整体插入
机械惰性替代组织。与长骨不同,长骨是通过
软骨内骨化、颅顶和牙周骨具有其独特的特点。
膜内骨化的方式,这是通过逐步完成的
一种富含胶原和蛋白多糖的特殊细胞外蛋白基质的矿化。
当颅骨和/或牙周骨因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,但也影响独特的细胞外骨
维持持续骨再生的有益信号环境的基质
和替补。在本申请中,我们重点介绍了最近描述的一种小型
分子介体,SETD7组蛋白赖氨酸甲基转移酶抑制剂PFI-2,在我们的
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、纤维连接蛋白和骨钙素。在动物研究中,PFI-2已经证明
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%的临界颅骨新骨覆盖率
缺陷。为这些令人兴奋的新发现提供了一种可能的机制,我们有
证明PfI-2抑制SETD7介导的-连环蛋白甲基化,导致核
-连环蛋白易位和骨基质蛋白转录激活
刺激与新骨形成有关的其他过程,如细胞增殖和
差异化。在目前的应用中,我们试图开发PFI-2的S潜力用于颅脑和
牙周骨再生,定义PFI-2触发新骨的机制(S)
细胞外基质沉积,以及足够稳定的工程支架以提供模板
用于未来临床应用和患者的PFI-2纳米微球控制释放
关心。
英文摘要
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.
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专著(0)
科研奖励(0)
会议论文
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海外基金