Broad objectives and specific aims. Shwachman-Diamond syndrome (SDS) is caused in most patients by loss-of-function mutations in the SBDS gene. The long-term objective of this proposal is to rescue SDS cellular defects through targeted manipulation of eIF6 activity. We will pursue this through two aims: 1) characterizing the biochemical mechanisms by which eIF6 mutations and post-translational modifications influence cellular function and 2) characterizing small-molecule modulators of eIF6. Background/rationale. eIF6 activity is well-defined by its ability to control the biogenesis, maturation, and availability of 60S ribosomes through regulated binding to the 60S subunit. Substantial evidence demonstrates that modulation of eIF6 activity can rescue the SDS phenotype. Moreover, our laboratory has demonstrated that eIF6 activity can be regulated by specific signaling pathways and that eIF6 mutations capable of rescuing SDS are non-toxic, providing a strong therapeutic foundation.
Research design and methods. To accomplish the first aim, we will build upon our established findings that eIF6 phosphorylation is crucial for its regulatory activity. We will comprehensively explore the biochemical networks surrounding eIF6's phosphorylated C-terminal domain using proximity labeling and related techniques. We will also define if a phosphatase that associates with eIF6 is a good pharmacological target. For the second aim, we will design and validate an enhanced array of small molecules targeting eIF6, leveraging the expertise and proprietary tools our laboratory has developed since discovering eIF6's therapeutic potential. Anticipated outcomes. Upon successful completion, this proposal will make a step forward in the strategy for therapeutic modulation of eIF6 activity in SDS patients.
Research design and methods. To accomplish the first aim, we will build upon our established findings that eIF6 phosphorylation is crucial for its regulatory activity. We will comprehensively explore the biochemical networks surrounding eIF6's phosphorylated C-terminal domain using proximity labeling and related techniques. We will also define if a phosphatase that associates with eIF6 is a good pharmacological target. For the second aim, we will design and validate an enhanced array of small molecules targeting eIF6, leveraging the expertise and proprietary tools our laboratory has developed since discovering eIF6's therapeutic potential. Anticipated outcomes. Upon successful completion, this proposal will make a step forward in the strategy for therapeutic modulation of eIF6 activity in SDS patients.