Upstate News

March 22, 2010
Doretta Royer 315 464-4833

Breakthrough research on cilia may provide clues to new therapies to fight disease

SYRACUSE, N.Y. — A team of investigators, led by Peter D. Calvert, Ph.D., of Upstate Medical University, has made a major breakthrough in research regarding degenerative and neoplastic diseases, such as cancer, using an experimental strategy and mathematical analyses they had developed in the laboratory.

The result of their work has allowed one of the most prevalent hypotheses in cell biology and medicine—that the bases of cilia restrict proteins from entering or exiting the ciliary compartments—to be rejected for soluble proteins. The transport of proteins to and from cilia is crucial for normal cell function and survival.

This discovery allows researchers to focus their efforts on finding other mechanisms for the confinement of soluble proteins to the cilia. The study appears in the March issue of the Journal of General Physiology.

Cilia are thin, hair-like projections emanating from most mammalian cells. Their function is well understood in only a few cell types, which include the photoreceptor cells in the retina, but it is clear that they are vital to normal cell function and to human health.

“Over the last decade hundreds of genetic mutations that lead to devastating, multiple organ diseases, including those causing blindness and deafness, cancer, kidney disease, obesity, mental retardation and many others, have been attributed to genes that encode proteins that are involved in the construction, maintenance, signaling or transport of molecules within cilia,” said Calvert, assistant professor of ophthalmology and adjunct assistant professor of biochemistry and molecular biology at Upstate. “Understanding how cilia manage these tasks is of paramount importance for finding therapies and cures for these debilitating and life-threatening diseases.”

Calvert adds that one of the major questions faced by scientists studying cilia is how proteins are transported to this tiny structure and how, once they arrive there, they are retained.

“One of the favorite mechanisms proposed is that specialized transport molecules deliver proteins into the cilium where they are then trapped by some sort of barrier that prevents them from diffusing back into the cell body,” said Calvert. “The same barrier was thought to prevent non-cilium proteins from entering this exclusive organelle. This idea was difficult to test because cilia are smaller than can be resolved by even the most powerful optical microscopes.

Calvert and his colleagues developed an experimental strategy and mathematical analyses that allowed them to break the resolution limit and address the question of whether or not there is a barrier to diffusion of soluble proteins within the cilia of rod photoreceptors.

They measured the diffusive movement of a genetically engineered photoactivatable green fluorescent protein into the cilia of rod photoreceptors in the eyes of African clawed frogs. They found that the rod cilium did not slow the diffusion of this soluble protein more than other parts of the rod cell and it did not stop it from moving between areas of the cell bridged by the cilium, leading to the rejection of the hypothesis that the cilium acts as a barrier to the movement of soluble proteins.

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