COMBINATORIAL GENE THERAPY FOR BONE REGENERATION

骨再生组合基因疗法

• 批准号: 8050640
• 负责人: Renny Theodore Franceschi
• 金额: $ 31.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8050640
• 关键词: Adenovirus Vector; Adenoviruses; BMP2 gene; Basic Science; Biological; Biological Process; Bone Development; Bone Regeneration; Calvaria; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell Proliferation; Cephalic; Complementary DNA; Defect; Development; Differentiation and Growth; Event; FGF2 gene; Femur; Fibroblast Growth Factor Receptors; Fracture; Fracture Healing; Gene Expression; Genetic; Healed; Implant; In Vitro; Individual; Injection of therapeutic agent; Laboratories; MAP Kinase Gene; Marrow; Measures; Mesenchymal; Modeling; Mutation; Natural regeneration; Osteoblasts; Osteogenesis; Pathway interactions; Peptide Signal Sequences; Play; Population; Pre-Clinical Model; Process; Protein Isoforms; Protein Secretion; Reagent; Regulation; Retroviridae; Rodent Model; Role; Signal Transduction; Site; Stem cells; Stromal Cells; System; Testing; Time; Translational Research; base; bone; bone healing; combinatorial; comparative efficacy; gene therapy; healing; improved; in vivo; long bone; novel; osteogenic; osteoprogenitor cell; overexpression; progenitor; regenerative; repaired; response; selective expression; subcutaneous; vector

DESCRIPTION (provided by applicant): Gene therapy approaches involving constitutive overexpression of cDNAs encoding individual BMPs can induce bone formation and partially repair cranial and long bone defects as shown by this laboratory. However, this strategy is limited by the availability of BMP-responsive osteoprogenitor/stem cells at the regeneration site and lack of control over the timing and duration of regenerative factor expression. The underlying hypothesis of this competitive renewal is that bone regeneration can be greatly improved if gene therapy is used to mimic the natural processes of bone development and fracture repair characterized by the participation of multiple growth/differentiation factors whose expression is under tight temporal control. Of particular importance are factors such as BMPs that may function as heterodimers to stimulate progenitor differentiation and FGF2 that controls progenitor proliferation. This project, which contains both translational and basic science components, will compare the efficacy of regenerative approaches in well-defined preclinical models as well as explore underlying mechanisms by achieving the following specific aims: Aim 1. Evaluate actions of an adenovirus expressing FGF2 (AdFGF2) on osteoprogenitor cell proliferation and differentiation in vitro and in vivo with or without Ad BMPs. Hypothesis: AdFGF2 can expand the population of osteogenic precursors at regeneration sites to enhance bone formation. Aim 2. Use inducible gene expression systems to control the timing, duration and sequence of osteogenic factor synthesis. Hypothesis: Enhanced control of osteogenesis can be achieved using regulated gene expression to control the timing, duration and sequence of proliferative versus osteoqenic signals. This project will test novel regenerative concepts involving cooperative interactions between proliferative and osteogenic factors and temporal regulation of factor synthesis using simple rodent models. Approaches developed will provide proof of principle of the eventual development of new therapies for bone regeneration that mimic natural biological processes by providing temporal control over regenerative events.

描述（由申请人提供）：如本实验室所示，涉及编码单个BMP的cDNA的组成型过表达的基因治疗方法可以诱导骨形成并部分修复颅骨和长骨缺损。然而，这种策略受到BMP-反应性骨祖细胞/干细胞在再生部位的可用性以及缺乏对再生因子表达的时间和持续时间的控制的限制。这种竞争性更新的基本假设是，如果基因治疗用于模拟骨发育和骨折修复的自然过程，其特征在于多种生长/分化因子的参与，其表达受到严格的时间控制，则可以大大改善骨再生。特别重要的是因子，如BMP，其可作为异源二聚体起作用以刺激祖细胞分化，和FGF 2，其控制祖细胞增殖。该项目包含转化和基础科学部分，将在明确的临床前模型中比较再生方法的功效，并通过实现以下具体目标探索潜在机制： 目标1。评价表达FGF 2的腺病毒（AdFGF 2）在体外和体内有或没有Ad BMP的情况下对骨祖细胞增殖和分化的作用。假设：AdFGF 2可以扩大再生部位的成骨前体细胞群，从而促进骨形成。 目标二。使用诱导基因表达系统来控制成骨因子合成的时间、持续时间和顺序。假设：通过调节基因表达来控制增殖信号与成骨信号的时间、持续时间和顺序，可以实现对骨生成的增强控制。 这个项目将测试新的再生概念，涉及合作之间的相互作用，增殖和成骨因子和时间调节因子合成使用简单的啮齿动物模型。所开发的方法将为最终开发用于骨再生的新疗法提供原理证明，该新疗法通过提供对再生事件的时间控制来模拟自然生物过程。

项目成果

Combinatorial gene therapy with BMP2/7 enhances cranial bone regeneration.

• DOI: 10.1177/154405910808700906
• 发表时间: 2008-09
• 期刊: JOURNAL OF DENTAL RESEARCH
• 影响因子: 7.6
• 作者: Koh, J. T.;Zhao, Z.;Wang, Z.;Lewis, I. S.;Krebsbach, P. H.;Franceschi, R. T.
• 通讯作者: Franceschi, R. T.

Patterning expression of regenerative growth factors using high intensity focused ultrasound.

使用高强度聚焦超声对再生生长因子进行模式化表达。

• DOI: 10.1089/ten.tec.2013.0518
• 发表时间: 2014
• 期刊: Tissue engineering. Part C, Methods
• 作者: Wilson,ChristopherG;Martín-Saavedra,FranciscoM;Padilla,Frédéric;Fabiilli,MarioL;Zhang,Man;Baez,AlexanderM;Bonkowski,ChristopherJ;Kripfgans,OliverD;Voellmy,Richard;Vilaboa,Nuria;Fowlkes,JBrian;Franceschi,RennyT
• 通讯作者: Franceschi,RennyT

Temporal and spatial patterning of transgene expression by near-infrared irradiation.

• DOI: 10.1016/j.biomaterials.2014.06.009
• 发表时间: 2014-09
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Martin-Saavedra, Francisco M.;Cebrian, Virginia;Gomez, Leyre;Lopez, Daniel;Arruebo, Manuel;Wilson, Christopher G.;Franceschi, Renny T.;Voellmy, Richard;Santamaria, Jesus;Vilaboa, Nuria
• 通讯作者: Vilaboa, Nuria

The effects of Runx2 immobilization on poly (epsilon-caprolactone) on osteoblast differentiation of bone marrow stromal cells in vitro.

• DOI: 10.1016/j.biomaterials.2010.01.029
• 发表时间: 2010-04
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Zhang, Ying;Deng, Xiaopei;Scheller, Erica L.;Kwon, Tae-Geon;Lahann, Joerg;Franceschi, Renny T.;Krebsbach, Paul H.
• 通讯作者: Krebsbach, Paul H.

Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness.

• DOI: 10.1016/j.actbio.2013.03.027
• 发表时间: 2013-07
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Fabiilli, Mario L.;Wilson, Christopher G.;Padilla, Frederic;Martin-Saavedra, Francisco M.;Fowlkes, J. Brian;Franceschi, Renny T.
• 通讯作者: Franceschi, Renny T.