SPARC and the Differentiation of Transparent Lens Fibers

描述(申请人提供)：SPARC(酸性分泌蛋白，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、损伤和修复方面表现突出。它属于 一类分泌的糖蛋白，虽然在结构上 不同的，调节细胞和细胞外基质(ECM)之间的相互作用。 SPARC已被证明专门用于a)抑制细胞周期，b)防止或 破坏细胞黏附，c)使细胞对某些生长的反应失活 包括碱性成纤维细胞生长因子(bFGF或FGF2)在内的因子，d)调节 ECM产生，e)与特定的胶原蛋白结合，包括基底的胶原蛋白 膜，和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 破坏SPARC基因。虽然SPARC-/-小鼠是存活的和有生育能力的， 与结缔组织相关的表型异常。这个 然而，主要的显性表型是出现豆状混浊。 1-2个月。出生后8mo左右发展为成熟性白内障。这个 SPARC对SPARC基因缺失小鼠晶状体透明度影响的解释如下 这是未知的，并构成了这一提议的基础。我们将检验这一假设 SPARC通过1)调节晶状体上皮细胞分化 碱性成纤维细胞生长因子激活的信号通路(S)2)对晶状体细胞-细胞的影响 细胞-晶状体囊(ECM)相互作用。我们的假设是基于 以下前提：a)整个晶状体纤维分化，基底面 增殖、迁移和伸长的纤维直接连接到 包膜的ECM，其中包含SPARC，b)发育和纤维 已知分化受FGF2调节，以及c)细胞分化 在晶状体中，从胎儿发育的早期开始，一直受到严格的控制 动物的寿命(即使是微小的干扰也很可能被记录为 透镜显影过程中的错误，这些错误可能直到 成年期，如白内障)。因此，提出的实验解决了 细胞上皮细胞-细胞外基质-相互作用在晶状体透明度和 为微分学中的微扰提供了一个新的模型，它可能是 在以后的生活中表现出来的。

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.