The vascular smooth muscle cell (VSMC) is a critical participant in the development of obstructive vascular disease (arteriosclerosis, restenosis after balloon angioplasty, and transplant vasculopathy). In response to vascular injury, the SMC undergoes a change in phenotype-from that of a quiescent/differentiated cell to one that dedifferentiates, proliferates, and elaborates extracellular matrix (ECM). Members of the Kruppel- like family of zinc finger transcription factors are critical regulators of cellular growth and differentiation. We have identified a novel member of this family expressed in both the heart and vasculature termed CKLF (Cardiovascular Kruppel-like Factor). Our preliminary data support a role for CKLF in VSMC differentiation, proliferation, and ECM production.
Aim 1 is to identify the CKLF repression domain and generate a dominant negative (CKLFdn) using reporter gene studies.
Aim2 is to assess the effect of retroviral overexpression of CKLF and CKLFdn on growth, differentiation, TGFbI levels, and ECM production in smooth muscle cells.
Aim3 is to determine the function of CKLF in vivo by generating null mice through homologous recombination. These studies may allow for novel strategies in the treatment of occlusive vascular disease.
| Otteson, Deborah C; Liu, Yuhui; Lai, Hong et al. (2004) Kruppel-like factor 15, a zinc-finger transcriptional regulator, represses the rhodopsin and interphotoreceptor retinoid-binding protein promoters. Invest Ophthalmol Vis Sci 45:2522-30 |
