Tribbles homolog 3 and BMP-2 induced bone formation

Tribbles 同源物 3 和 BMP-2 诱导骨形成

基本信息

批准号：
10397112
负责人：
Min Lee
金额：
$ 36.68万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-08 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397112
关键词：
Adverse effects BMP2 gene Binding Bone Morphogenetic Proteins Bone Regeneration Cell Differentiation process Clinical Complement Cyst DNA Data Defect Development Dose Employment Feedback GTP-Binding Protein alpha Subunits, Gs Gene Transfer Genes Genetic Transcription Goals Health Histologic Homologous Gene In Vitro Liposomes Mandible Mechanics Mediating Mesenchymal Mesenchymal Differentiation Mesenchymal Stem Cells Modality Modeling Molecular Target Osteoblasts Osteogenesis PPAR gamma Pathway interactions Persons Phospholipids Play Proteins Proteolysis Public Health RNA Interference Rattus Research Role Safety Signal Transduction Small Interfering RNA Structure System Testing Therapeutic Transfection Treatment Efficacy Ubiquitin Viral Insertional Mutageneses adverse outcome antagonist base bone bone morphogenetic protein receptors bone repair clinical application clinical efficacy clinical translation improved in vitro activity knock-down lipid biosynthesis microCT milligram nanocarrier nanocomplexes novel osteogenic osteogenin osteoinductive factor overexpression particle response skeletal small molecule therapeutic gene

项目摘要

Abstract Although bone morphogenetic protein-2 (BMP-2) is believed to be the most potent osteoinductive factor available for bone regeneration, its clinical application requires supraphysiological BMP doses that increase inappropriate adipogenesis and cyst-like bone formation. Therefore, recent promising alternative strategies are toward promoting pro-osteogenic activity of BMPs while simultaneously suppressing their adverse effects. Recent studies suggest important roles of tribbles homologs proteins in development and cellular differentiation. In response to BMP stimulation, in particular, tribbles homolog 3 (Trb3) is dissociated from BMP receptor and degrades Smad ubiquitin regulatory factor 1 (Smurf1), a negative regulator of BMP receptor-regulated Smads. Moreover, Trb3 has been shown to bind and suppress peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis. Thus, Trb3 may be a promising molecular target to enhance BMP-2 induced osteogenesis and reduce adverse adipogenesis. Upon BMP stimulation, however, BMP efficacy is greatly reduced due to the enhanced expression of natural BMP antagonists to auto-regulate endogenous BMP-2 levels. Thus, the potency of Trb3 in BMP treatments can be enhanced by inhibiting expression of BMP antagonists such as noggin. The objective of this study is to investigate whether overexpression of Trb3 and simultaneous abrogation of BMP antagonism can enhance BMP-induced osteogenesis and bone formation quality while lowering exogenous BMP requirement. The specific hypothesis is that the augmentation of Trb3 expression combined with the employment of noggin suppression can enhance bone formation by activation of Smad pathway and suppression of PPARγ, tested in the following aims. In Aim 1, we will evaluate whether Trb3 overexpression can synergistically enhance bone formation with BMP-2 in a rat critical size mandibular defect (MD). We will also apply high dose BMP-2 to induce adverse cyst-like bone formation in the MD model and test whether Trb3 overexpression can reduce the BMP-2 induced adverse outcomes and improve bone formation quality. In addition, we will determine whether the positive Trb3 effects are dependent on Smurf1 and PPARγ activities in vitro. Next in Aim 2, we will stimulate endogenous BMP signaling by downregulating noggin using an RNAi strategy and evaluate the synergistic effect of noggin suppression on Trb3-induced bone formation in the MD model. We will subsequently determine whether Trb3 expression + noggin suppression can lower total BMP-2 dose requirements or even eliminate use of exogenous BMP-2 without compromising osteogenic efficacy. Finally in Aim 3, we will further elaborate our complementary bone formation strategy (Trb3 expression + noggin suppression) toward clinical translations via use of appropriate carriers that deliver these therapeutic genes in much safer and efficient manners based on our novel non-phospholipid liposomal systems. Successful completion of these studies will identify a new strategy to improve clinical efficacy and safety of current BMP therapeutics by regulating expression of Trb3 and noggin for enhanced bone repair.

抽象的尽管骨形态发生蛋白-2 (BMP-2) 被认为是最有效的骨诱导因子可用于骨再生，其临床应用需要增加超生理BMP剂量因此，最近有希望的替代策略是不适当的脂肪生成和囊肿样骨形成。促进 BMP 的促成骨活性，同时抑制其不利影响。最近的研究表明 tribbles 同源蛋白在发育和细胞分化中发挥重要作用。特别是，响应 BMP 刺激，tribbles 同源物 3 (Trb3) 从 BMP 受体解离并降解 Smad 泛素调节因子 1 (Smurf1)，它是 BMP 受体调节的 Smad 的负调节因子。此外，Trb3 已被证明可以结合并抑制过氧化物酶体增殖物激活受体-γ (PPARγ)，PPARγ 是一种因此，Trb3 可能是增强 BMP-2 诱导的有前途的分子靶标。然而，在 BMP 刺激下，BMP 的功效非常显着。由于天然 BMP 拮抗剂的表达增强而自动调节内源性 BMP-2，从而减少因此，可以通过抑制 BMP 的表达来增强 Trb3 在 BMP 治疗中的效力。拮抗剂如 noggin 本研究的目的是调查 Trb3 和 Trb3 是否过度表达。同时消除 BMP 拮抗作用可增强 BMP 诱导的成骨和骨形成的具体假设是 Trb3 的增强。表达与头蛋白抑制相结合可以通过激活 Smad 通路和 PPARγ 抑制，在以下目标中进行测试，我们将评估是否。 Trb3过表达可以与BMP-2在大鼠临界尺寸下颌骨中协同增强骨形成我们还将应用高剂量的 BMP-2 在 MD 模型中诱导不良的囊肿样骨形成。并测试Trb3过表达是否可以减少BMP-2引起的不良后果并改善骨质此外，我们将确定 Trb3 的正效应是否依赖于 Smurf1 和接下来的目标 2，我们将通过下调 noggin 来刺激内源性 BMP 信号传导。使用 RNAi 策略并评估 noggin 抑制对 Trb3 诱导的骨的协同作用我们随后将确定是否Trb3表达+ noggin抑制。可以降低 BMP-2 总剂量需求，甚至消除外源 BMP-2 的使用而不影响最后，在目标 3 中，我们将进一步阐述我们的补充骨形成策略。（Trb3 表达 + noggin 抑制）通过使用适当的载体实现临床转化基于我们的新型非磷脂脂质体，以更安全、更有效的方式治疗这些基因成功完成这些研究将确定提高临床疗效和的新策略。通过调节 Trb3 和 noggin 的表达来增强骨修复，从而提高当前 BMP 疗法的安全性。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Smoothened agonist sterosome immobilized hybrid scaffold for bone regeneration.

用于骨再生的平滑激动剂立体体固定混合支架。

DOI：
发表时间：
2020
期刊：
影响因子：
13.6
作者：
Lee, Chung;Kim, Soyon;Fan, Jiabing;Hwang, Hee Sook;Aghaloo, Tara;Lee, Min
通讯作者：
Lee, Min

Generation of Small RNA-Modulated Exosome Mimetics for Bone Regeneration.

用于骨再生的小 RNA 调节外泌体模拟物的生成。

DOI：
10.1021/acsnano.0c05122
发表时间：
2020-09-22
期刊：
ACS nano
影响因子：
17.1
作者：
Fan J;Lee CS;Kim S;Chen C;Aghaloo T;Lee M
通讯作者：
Lee M

Microporous methacrylated glycol chitosan-montmorillonite nanocomposite hydrogel for bone tissue engineering.

用于骨组织工程的微孔甲基丙烯酸乙二醇壳聚糖-蒙脱土纳米复合水凝胶。

DOI：
发表时间：
2019
期刊：
影响因子：
16.6
作者：
Cui, Zhong;Kim, Soyon;Baljon, Jessalyn J;Wu, Benjamin M;Aghaloo, Tara;Lee, Min
通讯作者：
Lee, Min

Enhanced Osteoinductivity of Demineralized Bone Matrix with Noggin Suppression in Polymer Matrix.

通过聚合物基质中的 Noggin 抑制增强脱矿骨基质的骨诱导性。

DOI：
发表时间：
2021-01
期刊：
影响因子：
3.7
作者：
Chen, Chen;Rehnama, Matthew;Kim, Soyon;Lee, Chung;Zhang, Xiao;Aghaloo, Tara;Fan, Jiabing;Lee, Min
通讯作者：
Lee, Min

Bone-Targeting Exosome Mimetics Engineered by Bioorthogonal Surface Functionalization for Bone Tissue Engineering.

通过生物正交表面功能化设计的骨靶向外泌体模拟物，用于骨组织工程。

DOI：
发表时间：
2023-02-22
期刊：
影响因子：
10.8
作者：
Lee, Chung;Fan, Jiabing;Hwang, Hee Sook;Kim, Soyon;Chen, Chen;Kang, Minjee;Aghaloo, Tara;James, Aaron W;Lee, Min
通讯作者：
Lee, Min