Progressive scoliosis deformity in intervertebral disc

描述（由申请人提供）：进行性脊柱畸形（特别是脊柱侧凸和脊柱滑脱）在青春期生长高峰期进展最为迅速。在脊柱侧凸（包括神经肌肉型、先天性和特发性形式）中，这种进展包括椎体和椎间盘在冠状面楔入畸形的增加，以及其他面较小程度的畸形。虽然机械调节的软骨内生长似乎在很大程度上导致了椎体楔入，但椎间盘日益变形的机制在很大程度上是未知的，可能是非常不同的，因为伴随青少年椎体生长的椎间盘生长很小。拟议的研究将确定椎间盘如何响应发生在骨骼未成熟脊柱侧凸的改变应力。在脊柱侧凸中表现出椎体楔入的未成熟大鼠尾巴模型将被扩展，以确定椎间盘在成角畸形和压缩载荷下的变化。将比较持续压缩和持续成角的三种排列长达5周。将测量加载和/或变形的和相邻的控制盘，以确定形态学、结构和机械变化、环组织组成（包括凸面和凹面）、蛋白质合成和细胞结构。蛋白质合成将与椎间盘组织合成和降解的主要蛋白质的基因表达一起进行评估。研究结果将根据整体假设进行解释，即脊柱侧凸进展的椎间盘组成部分是由机械介导的凹侧椎间盘的重塑和退变引起的，凹侧椎间盘长期负荷更大。设计早期临床干预措施以预防脊柱侧凸进展的主要挑战是脊柱侧凸在青春期进展的未知机制以及缺乏准确的检测来识别潜在的进行性畸形（预后）。提出的工作提供了对畸形进展的更好理解，允许设计新的治疗方法来恢复脊柱的对称生长。这些方法可能包括支架设计的改进，肌肉康复的新可能性，以及旨在早期微创脊柱生长修复的外科手术。

DESCRIPTION (provided by applicant): Progressive spinal deformities (notably scoliosis and spondylolisthesis) progress most rapidly during the adolescent growth spurt. In scoliosis (including neuromuscular, congenital and idiopathic forms) this progression involves increasing wedging deformity of the vertebrae and discs in the coronal plane, together with lesser magnitudes of deformity in other planes. While it appears that mechanically modulated endochondral growth is responsible in large part for the progressive vertebral wedging, the mechanism by which intervertebral discs become increasingly deformed is largely unknown and probably very different, since there is minimal growth of intervertebral discs accompanying adolescent vertebral growth. The proposed studies will determine how intervertebral discs respond to the altered stress that occurs in a skeletally immature spine with scoliosis. A skeletally immature rat tail model that has demonstrated vertebral wedging as seen in scoliosis will be extended to determine the changes in the intervertebral disc with angulation deformity and compressive loading. Three permutations of sustained compression and sustained angulation for up to 5 weeks will be compared. Loaded and/or deformed and adjacent control discs will be measured to determine morphological, structural and mechanical changes, annulus tissue composition (including convex and concave sides), protein synthesis and cellularity. Protein synthesis will be evaluated along with gene expression for major proteins involved in synthesis and degradation of disc tissue. The findings will be interpreted with reference to the overall hypothesis that the intervertebral disc component of scoliosis progression results from mechanically-mediated remodelling and degeneration of the intervertebral disc on the concave side, which is chronically more heavily loaded. The major challenges in designing early interventions clinically to prevent scoliosis progression are the unknown mechanisms of scoliosis progression during adolescence and absence of accurate tests to identify potentially progressive deformities (prognosis). The proposed work provide improved understanding of deformity progression to permit design of novel therapeutic approaches to restore symmetrical growth of the spine. These approaches may include improvements in brace design, new possibilities for muscle rehabilitation, and surgical procedures aimed at early, minimally invasive modification of spinal growth.