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）：涉及编码单个BMP的cDNA构成过表达的基因治疗方法可以诱导骨形成，并部分修复该实验室所示的颅骨和长骨缺损。但是，该策略受到再生位点上BMP响应性骨基元细胞/干细胞的可用性的限制，并且缺乏对再生因子表达的时间和持续时间的控制。这种竞争性更新的基本假设是，如果使用基因治疗来模仿骨发育和断裂修复的自然过程，其表达受到严格的时间控制，可以大大改善骨骼再生。尤其重要的是诸如BMP之类的因素，这些因素可能是刺激祖细胞分化和控制祖细胞增殖的FGF2的异二聚体。该项目既包含翻译和基础科学组成部分，它将比较定义明确的临床前模型中再生方法的功效，并通过实现以下特定目的来探索潜在的机制： AIM 1。评估表达FGF2（ADFGF2）在体外和没有AD BMP的体内和体内分化的腺病毒的作用。假设：ADFGF2可以在再生位点扩大成骨前体的种群，以增强骨形成。 目标2。使用诱导基因表达系统来控制成骨因子合成的时间，持续时间和序列。假设：可以使用调节的基因表达来控制对成骨的控制，从而控制增殖和骨基因信号的时间，持续时间和序列。 该项目将测试新的再生概念，这些概念涉及增生性和成骨因子之间的合作相互作用以及使用简单啮齿动物模型对因子合成的时间调节。开发的方法将提供最终开发骨再生疗法的原理证明，该疗法通过对再生事件的时间控制来模仿自然生物学过程。

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

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.

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.