Extracellular Matrix Impacts Angiogenesis and Growth Plate Repair

细胞外基质影响血管生成和生长板修复

• 批准号: 10668056
• 负责人: Melissa Krebs
• 金额: $ 16.89万
• 依托单位: COLORADO SCHOOL OF MINES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668056
• 关键词: Address; Affect; Alginates; Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiogenic Peptides; Animal Model; Antibodies; Area; Biocompatible Materials; Bone Growth; Cartilage; Child; Childhood; Chitosan; Chondrogenesis; Clinic; Clinical; Cues; Deformity; Development; Endothelial Cells; Environment; Epiphysial cartilage; Extracellular Matrix; Fracture; Goals; Growth; Histologic; Hyaluronic Acid; Hydrogels; Impairment; In Vitro; Injectable; Injury; Link; Modeling; Modification; Molecular Weight; Operative Surgical Procedures; Osteogenesis; Pathway interactions; Peptides; Physiological; Play; Prevention; Process; Rattus; Research; Role; Signal Pathway; Signal Transduction; Site; Skeleton; System; Technology; Tissues; Translating; Translations; Vascular Endothelial Growth Factors; Work; angiogenesis; biomaterial development; bone; cartilaginous; cell behavior; cost; disability; healing; in vivo; injured; innovation; long bone; microCT; novel; pediatric patients; prevent; protein aminoacid sequence; regenerative; regenerative therapy; repaired; response; tissue repair; transcriptome sequencing; treatment strategy

PROJECT SUMMARY Growth plate injuries, which account for 30% of all pediatric fractures, can impair bone growth and even halt it completely. For children who are still growing, these injuries can be devastating. The growth plate (or physis) is a cartilage region found at the end of all long bones in children and is responsible for longitudinal bone growth. It is a weak area of the developing skeleton and prone to injury. Once damaged, cartilage tissue within the growth plate can be replaced by unwanted bony tissue, forming a “bony bar”, which can lead to angular deformities or complete growth arrest. Pediatric patients who sustain these injuries may require multiple surgical interventions during childhood. Innovative treatment strategies that prevent initial bony bar formation, thus avoiding growth deformities and potential lifelong disability, are critically needed. The goal of this project is to develop clinically useful treatment strategies for growth plate injuries that prevent bony bar formation and associated growth problems. One approach is to target mechanisms responsible for unwanted bony repair tissue, which include angiogenic signaling pathways. These pathways are regulated at many levels and can be modulated by insoluble cues such as extracellular matrix factors. The modulation of these cues via a material-only system could provide significant benefit to ultimate translation of such a regenerative therapy. Our hypothesis is that targeted disruption of angiogenic signaling cascades after growth plate injury through insoluble cues such as extracellular matrix factors will inhibit angiogenesis and completely prevent bony bar formation. We will examine this with the following 2 aims: AIM 1: To quantify the impact of hyaluronic acid (HA) on the angiogenic response that occurs after growth plate injury. As HA is known to be important in angiogenic signaling, but as its effect can be varied in different physiologic settings and as its impact in the growth plate after injury has not been studied, here we will investigate varying molecular weights of HA. Angiogenesis and bony bar prevention will be evaluated in our rat model of growth plate injury using bulk RNA-seq, microCT, immunostaining and histological assessment. AIM 2: To quantify the impact of specific peptide sequences on the angiogenic response that occurs after growth plate injury. Here 4 different peptides with established inhibitory effects on angiogenesis and osteogenesis will be covalently linked to our alginate hydrogels to study their influence on cell behavior. This Aim will quantify the impact of these peptides on angiogenesis, osteogenesis, and chondrogenesis in vitro and on the angiogenesis and osteogenesis that occurs in vivo in a rat growth plate injury model, as quantified using bulk RNAseq, microCT, immunostaining, and histological assessment. This project will provide important information about the impact of extracellular matrix cues in de novo growth plate injury healing and bony bar formation, supporting the development of novel biomaterial-based approaches to preventing bony bar formation. Ultimately, we will translate the technology to larger animal models of growth plate injuries, and eventually into the clinic. This research will help address a critical unmet clinical need for children suffering from growth plate injuries.

项目摘要 生长板损伤占所有儿科骨折的30％，可能会损害骨骼的生长甚至停止 完全地。对于仍在成长的孩子，这些伤害可能是毁灭性的。生长板（或物理）是 在儿童所有长骨的末端发现的软骨区域，并导致纵向骨生长。 它是发育中的骨骼的薄弱区域，容易受伤。一旦损坏，软骨组织在生长内 板可以用不必要的骨组织代替，形成“骨棒”，这可能导致角畸形或 完全生长逮捕。维持这些伤害的儿科患者可能需要多次手术干预 在童年时期。创新的治疗策略可以防止最初的骨棒形成，从而避免增长 迫切需要畸形和潜在的终身残疾。该项目的目的是在临床上开发 生长板损伤的有用治疗策略，以防止骨棒形成和相关生长 问题。一种方法是靶向负责不需要的奖金修复组织的机制，其中包括 血管生成信号通路。这些途径在许多层面上受到调节，可以通过不溶性调节 诸如细胞外基质因子之类的线索。通过仅材料系统对这些提示的调制可以提供 这种再生疗法的最终翻译的重大好处。我们的假设是有针对性的破坏 生长板损伤后通过不溶性线索（例如细胞外基质）的血管生成信号传导级联 因素将抑制血管生成并完全防止骨形成。我们将使用 以下2个目标：目标1：量化透明质酸（HA）对发生的血管生成反应的影响 生长板损伤后。由于HA在血管生成信号中很重要，但是由于其作用可以变化 在不同的生理环境中，并且由于损伤后其对生长板的影响尚未研究，我们在这里 将研究HA的不同分子量。血管生成和预防奖金预防将在我们的 使用大量RNA-Seq，MicroCT，免疫染色和组织学评估的大鼠模型。目的 2：量化特定肽序列对生长后发生的血管生成反应的影响 板损伤。这里有4个不同的宠物，对血管生成和成骨作用有建立的抑制作用将 与我们的藻酸盐氢一起共价链接，以研究其对细胞行为的影响。这个目标将量化 这些宠物对体外和血管生成的血管生成，成骨和软骨发生的影响 在大鼠生长板损伤模型中体内发生的成骨发生，并使用大量RNASEQ，microct， 免疫染色和组织学评估。该项目将提供有关影响的重要信息 从头生长板损伤愈合和奖励棒形成中的细胞外基质提示，支持 开发新型基于生物材料的方法，以防止骨棒形成。最终，我们会的 将技术转化为更大的生长板损伤动物模型，并最终转化为诊所。这 研究将有助于满足患有生长板损伤的儿童的关键未满足临床需求。