STRUCTURAL, MECHANICAL, AND CELL BIOLOGICAL PROPERTIES OF THE CILIARY ZONULE

项目摘要。 一种称为睫状带的细胞外纤维系统悬挂晶状体并使其居中 眼睛。索状纤维断裂是许多眼科疾病的特征，并导致 晶状体脱位(异位晶状体)。编码小带蛋白的基因突变 对眼睛发育有深远的影响。除异位晶状体外，还包括 小球晶状体眼和高度轴性近视。这些观察结果支持这样一种观点，即 小带在眼睛发育中的作用不仅仅是将晶状体定位在光轴上。 为了深入了解小带的作用，我们开发了两种小鼠模型 最丰富的带状蛋白，纤维蛋白-1(FBN1)和潜伏的转化生长因子β结合蛋白2(LTBP2) 已被删除。在这两种模型中，小带最初都是合成的，但随着时间的推移，异位 小扁豆在所有动物身上都会发育。此外，LTBP2缺陷小鼠有微球晶状体和 FBN1缺陷小鼠患上晶状体诱导的青光眼。我们将利用这些小鼠模型 测试FBN1和LTBP2对结构和生物力学性能的特异性贡献 由带状纤维组成。我们还将测试长期存在的假设，即小带张力调节 晶状体萌发区的细胞增殖率，从而直接影响晶状体 尺码。总之，这些实验将提供对人类眼部表型的洞察 马凡综合征或Weill-Marchesani综合征的患者，遗传性疾病源于 FBN1和LTBP2分别发生突变。此外，由于微纤维(鞋底 带状纤维的成分)与身体其他部位的疾病过程有关 (例如，心血管疾病)对心脏进行的结构/功能研究的结果 纤毛小带有望具有广泛的临床意义。

Project Summary. A system of extracellular fibers called the ciliary zonule suspends and centers the lens in the eye. Breakage of zonular fibers is a characteristic of many ocular diseases and results in dislocation of the lens (ectopia lentis). Mutations in genes encoding zonular proteins have profound effects on ocular development. In addition to ectopia lentis, these include microspherophakia and high axial myopia. These observations support the notion that the zonule has a role in ocular development beyond merely positioning the lens on the optical axis. To gain insights into the role of the zonule, we have developed mouse models in which the two most abundant zonular proteins, fibrillin-1 (FBN1) and latent TGFbeta-binding protein 2 (LTBP2) have been deleted. In both models, the zonule is synthesized initially, but over time, ectopia lentis develops in all animals. Moreover, LTBP2-deficient mice have microspherophakia and FBN1 deficient mice develop lens-induced glaucoma. We will utilize these murine models to test the specific contributions of FBN1 and LTBP2 to the structure and biomechanical properties of zonular fibers. We will also test the long-standing hypothesis that zonular tension modulates the rate of cell proliferation in the germinative zone of the lens, thereby directly influencing lens size. Together, these experiments will provide insights into the ocular phenotypes of human patients with Marfan syndrome or Weill-Marchesani syndrome, heritable conditions arising from mutations in FBN1 and LTBP2, respectively. Furthermore, because microfibrils (the sole constituents of zonular fibers) are implicated in disease processes elsewhere in the body (cardiovascular disease, for example) the results of structure/function studies performed on the ciliary zonule are expected to have broad clinical relevance.