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

项目摘要。 称为睫状小带的细胞外纤维系统将透镜悬置在晶状体中央， 眼睛悬韧带纤维的断裂是许多眼部疾病的特征， 透镜脱位（晶状体异位）。编码悬韧带蛋白的基因突变， 对眼睛发育有深远影响。除了晶状体异位，这些包括 微球形晶状体眼和高度轴性近视。这些观察结果支持了这样一种观点，即 小带在眼睛发育中的作用不仅仅是将透镜定位在光轴上。 为了深入了解小带的作用，我们开发了小鼠模型，其中两个 最丰富的悬韧带蛋白，包括TGF-β 1（FBN 1）和潜在TGF-β结合蛋白2（LTBP 2） 已被删除。在这两种模型中，悬韧带最初是合成的，但随着时间的推移， 所有动物都有晶状体。此外，LTBP 2缺陷型小鼠具有微球形晶状体， FBN 1缺陷小鼠发生晶状体诱导的青光眼。我们将利用这些小鼠模型， 测试FBN 1和LTBP 2对结构和生物力学性能的特定贡献 小带纤维我们还将检验长期存在的假说，即悬韧带张力调节 透镜的萌发区中的细胞增殖速率，从而直接影响透镜 尺寸总之，这些实验将提供对人类眼表型的见解。 马凡氏综合征或Weill-Marchesani综合征患者，由以下疾病引起的遗传性疾病 FBN 1和LTBP 2的突变。此外，由于微纤维（鞋底） 小带纤维的成分）与身体其他部位的疾病过程有关 （例如，心血管疾病）对心脏进行结构/功能研究的结果 睫状小带预期具有广泛的临床相关性。

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.