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Major support for cataract study

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Scientists have long since cracked the codebook – the DNA molecule – that holds comprehensive genetic information about living organisms. They have also shown how specific information-rich regions within the DNA code, called genes, are copied into messenger molecules known as RNA.

Much less is known, though, about how cells control those messages – in precise cellular space and time – to produce the proteins that carry out a myriad of biological functions. And even less is known about how defects in these specialized gene control mechanisms cause eye diseases such as cataracts.

Salil Lachke, assistant professor of biological sciences at the University of Delaware, is investigating that in a project that has just won $1.95 million in support from the National Institutes of Health.

Specifically, he is studying the cellular and molecular processes that keep the lens of an eye transparent, an expansion of his extended research on cataract, the primary cause of blindness in the world. Using the bioinformatics tool he helped to develop – known as iSyTE (integrated Systems Tool for Eye gene discovery) – he has identified several new cataract-linked genes and is exploring how those that specifically produce proteins that bind to RNA are involved in lens development.

"Out of the estimated 22,000 genes in our cells, a large chunk – about 10 percent – code for proteins that are specialized to bind RNA molecules and control their fate, such as 'translating' their information to make other proteins," Lachke said. "However, very few such proteins have been studied so far, and even fewer have been directly linked to human disease. We think that mechanisms involving these RNA-binding proteins are important for the formation of lenses in embryonic development, and, in later stages, to keep them transparent."

In this five-year project, Lachke and researchers in his lab continue to explore lens development with a focus on how specific RNA-binding proteins control this process. They also plan to build a detailed biological gene regulatory circuit, similar to an electrical circuit, to better understand cellular operations and interactions.

One protein that binds with RNA – Celf1 – has been a focus of special interest. Lachke and his lab have demonstrated that mice always develop cataracts at birth whenever a Celf1 deficiency occurs during the lens development process.

Lachke said two collaborators – Luc Paillard at the Institute of Genetics and Development of Rennes University in France and Jeffrey Gross at the University of Pittsburgh School of Medicine – have found that Celf1 is also important in frogs and zebrafish, respectively, which would suggest a potentially powerful role in cataract disorders in all vertebrates, including humans.

"It's an opportunity to learn fundamental new lessons about the molecular basis of how these proteins are involved in controlling RNA information during organogenesis," he said. "Now we can ask sophisticated questions about which precise letters in an RNA sequence do these proteins bind, and what happens to these RNA messages after the proteins bind them – for example, is the RNA silenced, destroyed, or kept stable for making more protein? We are going to address these questions."

Cells "read" information in their DNA, copy it as RNA – in a process analagous to photocopying a specific page in a precious book – and use this RNA copy to make proteins. Much study has focused on the proteins that initiate the copying of DNA into RNA. Less is known about the proteins that control the reading of RNA.

Lachke recently published an article, to be featured on the cover of the journal Wiley Interdisciplinary Reviews: RNA, highlighting the limited knowledge of RNA-binding proteins and the challenges their study poses in eye development and disease.

All of that coding and regulation and processing hold important clues to developmental defects – the times and places where things go wrong – that Lachke and others are investigating in a quest to advance public health.

"Presently, the only cure to cataracts is surgery," he said. "Through this study, we hope to understand the molecules that help to make and keep a lens transparent."

Lachke hopes insights gained from these experiments will not only uncover fundamental principles in gene expression control, but also influence future non-invasive therapies to prevent cataracts.

The award is a competitive renewal of Lachke's previous NIH grant on post-transcriptional control in lens development.

Lachke earned bachelor's and master's degrees at the University of Pune, India, and earned his doctorate at the University of Iowa. He did postdoctoral work at Harvard Medical School and Brigham and Women's Hospital, and worked as an instructor in medicine at Harvard before joining the faculty at the University of Delaware in 2011.

His innovative research has been recognized with awards from many groups and foundations, including the Pew Charitable Trusts, which named Lachke a Pew Scholar in Biomedical Sciences in 2012.

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