Aberrant protein synthesis is associated with a variety of disease states such as cancer and neurodegeneration. The protein output per mRNA is strongly affected by a combination of cis elements and trans factors that together control the rate of recruitment of ribosomes to the 5?-untranslated region (5?-UTR). Different 5?-UTRs are sufficient to confer a thousand-fold range of translation output both in vivo and in vitro, but the mechanisms underlying these large effects are unknown in most cases. This proposal for an NIH K99/R00 Pathway to Independence Award seeks to understand the 5?-UTR regulatory code controlling mRNA translation by answering two fundamental questions: (1) what are the components of the code? And (2) what is the mechanism by which the components affect translational activity? To answer these questions Dr. Niederer will take advantage of a cellular condition where widespread changes in 5?-UTR usage have been observed- cancer. Using a novel technical approach Dr. Niederer will directly measure ribosome recruitment levels to thousands of 5?-UTR sequences that are differentially expressed in cancer cells (Aim 1). While the changes in 5?-UTR usage are well known, their affect on ribosome recruitment is more or less completely unknown. Therefore, these studies can be used to identify functional RNA elements. Then, a combination of biochemical and genetic studies will be used to identify the readers of these functional RNA elements (Aim 2). The results of this work are likely to reveal novel mechanisms of translation regulation, which will not only further our understanding of a fundamental cellular process but will also have implications for human health and disease. To complete these studies, Dr. Niederer will continue her training as a Postdoctoral Associate in the Molecular Biophysics and Biochemistry department at Yale University. During the K99 phase Dr. Niederer will receive invaluable training in computational methods to both identify functional RNA elements and deconvolute their contributions to ribosome recruitment. Additionally, after working almost exclusively with the model organism S. cerevisiae for over 10 years, she will expand her technical expertise to be able to conduct experiments in the context of human cells. Using these skills, in the R00 phase, Dr. Niederer will characterize the candidate readers and determine their role in supporting translational reprogramming. The Pathway to Independence award will allow Dr. Niederer to gain the necessary technical expertise and professional skills to become a competitive applicant for tenure track positions as a group leader.
Protein synthesis is misregulated in a number of diseases including cancer and neurodegeneration. I will investigate the features within mRNA that govern protein synthesis. Elucidating this process will lead to a better understanding of many cellular processes from development to adaptation and may also lead to more effective treatments for a variety of diseases.