A healthy ocular lens is essential for vision and a critical component of the eye as an organ system. It is a highly organized and intricate structure that is precisely suited for it's function. It's formation is dependent upon an appropriate regulation of the shift in the proliferative epithelial cells to differentiated, denucleated and elongated fiber cells. The long-term objective of this proposal is to understand the molecular mechanisms that regulate this process in vivo. The Griep lab has previously characterized transgenic mice which expressed human papilloma virus-16 E6 or E7 oncogenes in the lens. These viral oncoproteins serve as trans-dominant negative regulators of the function of p53 and the retinoblastoma (Rb) family of proteins. Expression of these oncoproteins leads to micropthalmia, cataracts and tumors that reflect aberrant proliferation and increased apoptosis. In the proposed studies, I will characterize the role that Rb and Rb- specific targets play in lens development. First, I propose to over- express Rb dominant negative mutants in the murine lens and examine the effects on proliferation, differentiation and apoptosis. Second, I propose to over-express the transcription factor, E2FI, a direct target of Rb and an important regulator of cell cycle progression. Finally, I will assess the contributions of the extra-cellular matrix and survival factors to this phenotype using both primary lens fiber cell culture and aggregation chimeras from E7 transgenic animals. Overall, these studies will contribute to our understanding of abnormal lens and cataract formation which in turn can facilitate treatment.
|McCaffrey, J; Yamasaki, L; Dyson, N J et al. (1999) Disruption of retinoblastoma protein family function by human papillomavirus type 16 E7 oncoprotein inhibits lens development in part through E2F-1. Mol Cell Biol 19:6458-68|