Young Innovator Award
As part of NIH's commitment to increasing opportunities for new scientists, it has created the NIH Director's New Innovator Award to support exceptionally creative new investigators who propose highly innovative projects that have the potential for unusually high impact.
Melanie Ohi recently received the highly competitive National Institutes of Health Young Innovator Award to study the structure and function of the spliceosome. Composed of both protein and RNA components this complex is responsible for removing introns from pre-mRNA to form mature message. Mistakes made by the splicing machinery, such as choosing the wrong sites to clip out the intron, can have dramatic effects on an organism, since each error can lead to a change in the protein-coding sequence of the mRNA and the possible synthesis of a defective protein. Not surprisingly, many genetic diseases and types of cancer originate with defects in pre-mRNA splicing. However, even though spliceosome activity is essential for maintaining cellular function, the extremely dynamic nature and large size of this complex has made it difficult to understand how this cellular machine actually works.
Using a structural technique called single particle cryo-electron microscopy (EM), the Ohi lab plans on generating 3D snapshots of the spliceosome stalled at distinct stages of assembly, catalysis, and disassembly. In addition, they will also begin building spliceosomal sub-complexes de novo using recombinant proteins. Studying the structures and functions of the large complexes will provide important information about overall spliceosome organization during each stage of pre-mRNA splicing, while understanding the organization and biochemical activity associated with spliceosomal sub-complexes will provide a mechanistic understanding for how the spliceosome is activated. The overall goal of this work is to generate the first structural based model for understanding how the spliceosome makes the dynamic transition from an inactive to an activated splicing machine.
When asked why she thought this project was selected for an Innovator Award, Melanie responded that “studying how the spliceosome functions has been a topic of intense research for over 20 years, but due to its large size and dynamic nature how this machine actually works still remains a mystery. Our approach is considered bold and innovative because we are proposing to focus both on mapping the overall organization of the entire 3 MDa complex using state of the art single particle EM techniques and on characterizing the function(s) associated with small sub-groups of spliceosomal proteins using biochemical and genetic approaches. I think it is the combination of taking both a top-down and bottom-up approach to understand spliceosome function and our use of a powerful combination of structural, biological, and biophysical techniques that made this proposal stand out to the reviewers.”