SPARC and the Differentiation of Transparent Lens Fibers

描述（由申请人提供）：分泌蛋白（分泌蛋白，酸性且富含 半胱氨酸）是重塑组织的主要成分，因此， 在形态发生、发育、损伤和修复中起重要作用。它属于 分泌糖蛋白的基质细胞类，尽管在结构上 不同的是，调节细胞和细胞外基质（ECM）之间的相互作用。 已经显示出特异性地a）抑制细胞周期，B）预防或 破坏细胞粘附，c）抑制细胞对某些生长的反应 包括碱性成纤维细胞生长因子（bFGF或FGF 2）的因子，d）调节 ECM的产生，e）与特定的胶原蛋白结合，包括基底的胶原蛋白 f）促进圆形细胞形状和肌动蛋白的重组 细胞骨架这些属性为有针对性的 基因的破坏。尽管β-/-小鼠是可存活和可生育的， 存在与结缔组织相关的表型异常。的 然而，主要的显性表型是晶状体混浊的出现， 1-2密苏里州出生后8个月进展为成熟白内障。的 对SPARC基因敲除小鼠中晶状体对透镜透明度影响的解释是 这是未知的，也是这个提议的基础。我们将检验这个假设， 晶状体上皮细胞通过以下方式调节透镜上皮细胞分化：1）调节 bFGF激活的信号通路，以及2）其对透镜细胞-细胞的影响 和细胞-ECM（透镜囊）相互作用。我们的假设是基于 以下前提：a）在整个透镜纤维分化过程中，基底表面 增殖、迁移和伸长的纤维直接附着在 包囊的ECM，其含有纤维，B）发育和纤维 已知细胞分化受FGF 2调节，和 在透镜中的作用从胎儿发育的早期就受到严格控制， 动物的生活（即使是轻微的扰动也可能被“记录”为 在透镜的开发过程中出现的错误， 成年期，例如，白内障）。因此，提出的实验解决了以下问题： 透镜透明度中细胞上皮-ECM相互作用的失调， 提供了一个新的模型，扰动微分，可以 在以后的生活中表现出来。

DESCRIPTION (provided by applicant): SPARC (secreted protein acidic and rich in cysteine) is a major component of remodeling tissues and, as such, features prominently in morphogenesis, development, injury, and repair. It belongs to the matricellular class of secreted glycoproteins that, although structurally dissimilar, regulate interactions between cells and extracellular matrix (ECM). SPARC has been shown specifically to a) inhibit the cell cycle, b) prevent or disrupt cell adhesion, c) inactivate cellular responses to certain growth factors including basic fibroblast growth factor (bFGF or FGF2), d) regulate ECM production, e) bind to specific collagens including those of the basement membrane, and f) promote a rounded cell shape and reorganization of the actin cytoskeleton. These properties provide a strong rationale for a targeted disruption of the SPARC gene. Although SPARC -/- mice were viable and fertile, there were phenotypic abnormalities associated with connective tissue. The major, dominant phenotype, however, was the appearance of lenticular opacity at 1-2 mo. after birth and progression to mature cataracts by 8 mo. The explanation for the effect of SPARC on lens transparency in SPARC-null mice is unknown and forms the basis for this proposal. We will test the hypothesis that SPARC regulates lens epithelial cell differentiation via 1) its modulation of signaling pathway(s) activated by bFGF, and 2) its effects on lens cell-cell and cell-ECM (lens capsule) interactions. Our hypothesis is based on the following premises: a) throughout lens fiber differentiation, the basal surface of proliferating, migrating, and elongating fiber is directly attached to the ECM of the capsule, which contains SPARC, b) development and fiber differentiation are known to be regulated by FGF2, and c) cell differentiation in the lens is rigorously controlled from early in fetal development throughout the life of the animal (even minor perturbances are likely to be "recorded" as errors in the development of the lens that might not be apparent until adulthood, e.g., cataracts). The experiments proposed thus address the role of dysregulation in cell epithelium-ECM-interaction in lens transparency and afford a novel model for perturbations in differentiation that could be manifested later in life.