Date of Award

12-2004

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Robert N. Moore, Albert T. Ichiki, Steve J. Kennel, Mark Sangster

Abstract

Ocular infection of Herpes Simplex Virus-1 (HSV-1) causes Herpetic Stromal Keratitis (HSK), which is a leading cause of infectious blindness. Although complex interactions of molecular and cellular events involve in the department of HSK, it has been known that angiogenesis is a key step for the HSK pathogenesis. Treatment of neutralizing antibody against vascular endothelial growth factor (VEGF) to inhibit VEGF activity reduced angiogenesis and HSK severity caused by infection of HSV-1 in mouse eyes. In addition, inactivation of cytokine which induces VEGF production and angiogenesis also reduced angiogenesis and HSK severity. Therefore, it has been proposed that VEGF or molecules which induce VEGF production or angiogenesis can be good target molecules for treating HSK. In this study, we investigated whether targeting VEGF or IL-1 receptor type I (IL-1RI) using RNAi technology could reduce angiogenesis in mouse eyes.

A general introduction and overview of RNAi were provided in Part I. Results in Part II demonstrated that intrastromal injection of VEGF short hairpin RNA (shRNA) could reduce VEGF production and angiogenesis caused by CpG motif in mouse eyes. Implantation of pellets containing bio-active CpG motifs following intrastromal injection with a plasmid expressing shRNA against VEGF reduced angiogenesis and VEGF production. Results in Part III showed that intrastromal injection of IL-1RI shRNA could reduce angiogenesis caused by IL-1O through reduction of VEGF production. The results in this dissertation indicate that targeting VEGF or IL-1RI using RNAi technology can reduce angiogenesis in mouse eyes. Additionally, these results imply that an eye is a suitable organ to apply RNAi technology. Thus, this technology may help to understand corneal biology as well as to treat corneal diseases in the near future.

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