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Ambati study published in PNAS
Date:4/6/2009

's population suffering from neovascular diseases. However, this first study did not address other forms of specialized endothelial cells that exist in the human body, including those that line the lymphatic system, a critical component of immune responses. The new study found that siRNAs block not only blood vessels but also lymphatic vessels. In the cornea, the clear part of the eye, injury often leads to the formation of both blood and lymphatic vessels. In fact, the formation of lymphatic vessels after corneal transplantation is purported to be a major mechanism through which transplant rejection occurs. Ambati's lab found that corneal injections of siRNA suppressed both blood and lymphatic vessel growth via endothelial cell toxicity.

Won Gil Cho, post-doctoral fellow, Dr. Romulo Albuquerque, and Dr. Mark Kleinman, researchers in the Ambati laboratory, also showed that siRNA directly activates TLR3, the first time this has been demonstrated in the literature. Addditionally, they showed, using time-lapse studies, that siRNA does not enter cells without a cell-permeating moiety such as cholesterol. This is important, because siRNA must enter cells in order to function as intended by specifically degrading intracellular messenger RNA bound for protein-forming machinery. Furthermore, this finding strengthens their finding that TLR3 positioned on the cell surface is responsible for mediating the toxic side-effects of siRNA. In concert with Sandro De Falco and Arturo Brunetti, researchers in Naples, Italy, they also found that siRNAs generically block blood and lymphatic vessel growth in muscle tissue as well. These findings illustrate this side effect of siRNA can occur in many parts of the body.

Ambati's lab also reported last year in the New England Journal of Medicine that siRNA is deleterious to other cell types, such as the retinal pigmented epithelium, which is involved in age-related macular degeneration.

"This may be a broadly imprinted
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Contact: Ann Blackford
ann.blackford@uky.edu
859-559-1964
University of Kentucky
Source:Eurekalert

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