Citrate Metabonegenic Regulation for the next Generation of Orthopedic Biomaterial Design

下一代骨科生物材料设计的柠檬酸代谢调节

• 批准号: 10116283
• 负责人: Jian Yang
• 金额: $ 33.4万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116283
• 关键词: 5' -AMP-activated protein kinase; Address; Anatomy; Animal Model; Animals; Architecture; Biocompatible Materials; Biomimetics; Bone Development; Bone Matrix; Bone Regeneration; Bone Tissue; Cell Culture Techniques; Cells; Cellular Metabolic Process; Cephalic; Chemicals; Chronic; Citrates; Complex; Consumption; Crystallization; Defect; Development; Developmental Process; Energy Metabolism; FRAP1 gene; Implant; Inflammation; Inflammatory Response; Knowledge; Mechanics; Mediating; Mesenchymal Differentiation; Mesenchymal Stem Cells; Metabolic; Minerals; Modeling; Molecular; Orthopedics; Osteoblasts; Osteogenesis; Pathway interactions; Performance; Phenotype; Physiology; Play; Process; Protein Biosynthesis; Protein Kinase; Proteins; Rattus; Regulation; Research; Role; Signal Transduction; Skeletal system; Testing; Tissue Engineering; Tissues; Translating; base; bone; design; extracellular; in vivo; mimetics; mineralization; next generation; novel; osteogenic; scaffold; stem cell differentiation; stem cells; uptake

Research Summary The objectives of this project are to elucidate an unexplored metabonegenic regulation of citrate for bone development, and to translate these understandings towards the design of novel biomimetic citrate-presenting bone biomaterials for orthopedic applications. Although significant progress has been made in the development of orthopedic biomaterials, the currently available materials are limited by their inabilities to mimic the native tissue composition, weak mechanical strength, minimal osteoinductivity, significant inflammatory responses, poor bone integration, and slow bone regeneration. We hypothesize that the uptake of extracellular citrate via transporter SLC13a5 could elevate cellular energy status through modulation of cell metabolism, which in turn leads to a facilitated osteogenic phenotype progression by inhibiting the activity of AMP-activated protein kinase (AMPK). This new citrate-based regulation of bone development is referred to as citrate metabonegenic regulation (Fig. 1). The identification of new and unexplored citrate-based strategies to promote osteogenic differentiation of mesenchymal stem cell can be harnessed to more efficiently design the next generation of biomimetic orthopedic biomaterials to address the limitations of the previous materials. To test our hypotheses and achieve the objectives of this project, three aims are proposed: Aim 1) to elucidate the metabonegenic regulatory effect of citrate for MSCs osteogenic differentiation; Aim 2) to apply the understandings of the citrate molecular mechanism in the design of biomimetic citrate-presenting biomaterials to mediate MSCs differentiation; Aim 3) To evaluate the in vivo performance of anatomically and chemically mimetic citrate-presenting scaffolds in a rat critically sized cranial bone defect model. It is very intriguing that the unprecedented knowledge on the unexplored citrate mechanism will enable us to design the next generation of biomimetic dynamic orthopedic implants that may present citrate signals in demand during cellular and tissue development. The understanding on the citrate metabonegenic regulation for bone stem cell culture and dynamic bone materials design will not only advance the field of bone tissue engineering, but also profoundly impact a wide array of other conditions such as MSC adipogenic differentiation since MSCs is multipotent and the adipogenic differentiation also has high energy demand.

研究总结 该项目的目标是阐明柠檬酸盐对骨的未探索的代谢成骨调节 开发，并将这些理解转化为新型仿生柠檬酸盐的设计 用于骨科应用的骨生物材料。尽管在这方面已经取得了重大进展 骨科生物材料的发展，目前可用的材料因其无法模仿而受到限制 天然组织成分、机械强度弱、骨诱导性极小、炎症显着 反应、骨整合不良和骨再生缓慢。我们假设细胞外物质的摄取 柠檬酸通过转运蛋白 SLC13a5 可以通过调节细胞代谢来提高细胞能量状态， 这反过来又通过抑制 AMP 激活的活性来促进成骨表型进展 蛋白激酶（AMPK）。这种新的基于柠檬酸盐的骨骼发育调节被称为柠檬酸盐 代谢成骨调节（图1）。确定新的和未经探索的基于柠檬酸盐的策略 促进间充质干细胞的成骨分化可用于更有效地设计 下一代仿生骨科生物材料可以解决以前材料的局限性。到 为了检验我们的假设并实现该项目的目标，提出了三个目标： 目标 1) 阐明 柠檬酸盐对MSCs成骨分化的代谢调节作用；目标 2) 应用 了解仿生柠檬酸盐生物材料设计中的柠檬酸盐分子机制 介导 MSC 分化；目标 3) 从解剖学和化学角度评估其体内性能 在大鼠临界尺寸颅骨缺损模型中模拟柠檬酸盐呈现支架。非常有趣的是 对未探索的柠檬酸机制的前所未有的了解将使我们能够设计下一个 生成仿生动态骨科植入物，在手术过程中可以呈现所需的柠檬酸盐信号 细胞和组织发育。柠檬酸对骨干细胞代谢成骨调节的认识 培养和动态骨材料设计不仅将推动骨组织工程领域的发展，而且 由于 MSC 是 多能性和成脂分化也有很高的能量需求。