Stromal injury results invariably in stromal scarring and in many instances impaired vision. Many in vivo and in vitro models have been used to study corneal wound healing. Importantly, evidence from these studies suggests that there are certain common biochemical events that occur in response to injury. Foremost amongst these are changes in the composition and organization of the stromal extracellular matrix. In addition, the presence of the glycosaminoglycan, heparan sulfate, within the corneal stroma has been noted in a number of injury models. The corneal stroma. is normally devoid of heparan sulfate, suggesting that its presence at sites of injury represents an integral component of the cellular response to injury. We have recently noted that the intracellular localization of heparan sulfate can be regulated by the state of the extracellular matrix. We found that a large fraction of the heparan sulfate proteoglycan (HSPG) expressed by corneal fibroblasts in culture is localized to the nucleus when cells were grown on a fibronectin containing matrix. Thus, the overall goals of this proposal are to identify the mechanisms and consequences of HSPG nuclear localization in stromal fibroblasts. We hypothesize that the nuclear translocation of HSPG is regulated by interactions between extracellular proteins and heparan sulfate chains. We propose that these interactions stimulate intracellular signaling events involving protein kinase C family members. We will evaluate possible consequences of nuclear HSPG including the likelihood that HSPG can be used as a macromolecular shuttle for extracellular proteins to access the nucleus.
The specific aims of this proposal are: 1. Define the mechanisms underlying HSPG nuclear translocation, and 2. Identify potential functional consequences of nuclear HSPG. These studies will have wide ranging implications throughout eye research and could reveal a previously undetected generalized mechanism for nuclear-extracellular communication. Information from these studies could provide the foundation for the development of a new generation of therapies aimed at facilitating corneal repair without scarring.
| Hsia, Edward; Richardson, Thomas P; Nugent, Matthew A (2003) Nuclear localization of basic fibroblast growth factor is mediated by heparan sulfate proteoglycans through protein kinase C signaling. J Cell Biochem 88:1214-25 |
