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.

项目总结