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

项目总结。

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.