The specific research goal of the Garner Laboratory is to investigate the role of translational control in human diseases. The process of mRNA translation, or protein synthesis, has been shown to be dysregulated in a number of disorders, including cancer and metabolic, neurodegenerative, viral and parasitic diseases; yet, targeting of this process remains an underexplored area for therapeutic development. In addition, despite our high-level understanding of translation, many fundamental questions regarding the detailed cellular mechanisms of translational control persist. We seek to solve these applied and basic science problems using interdisciplinary research approaches in chemical biology, medicinal chemistry and molecular, cellular and structural biology.
microRNA-Mediated Gene Silencing:
Following completion of the human genome project, it was revealed that only ~2% of our genome encodes for proteins, and the overwhelming majority is comprised of often highly conserved non-coding RNAs. One class of non-coding RNAs that has been found to play crucial roles in the development of human diseases is microRNAs (miRNAs or miRs). MicroRNAs comprise a large family of small, ~21-23 nucleotide single-stranded RNAs that have emerged as key post-transcriptional regulators of gene expression. To date, there are >2,500 predicted human miRNAs believed to control the activity of >60% of all protein-coding genes. Accordingly, alteration of miRNA expression, up- or downregulation, has been linked to cancer, obesity, diabetes, viral infections and autoimmune, inflammatory, neurodegenerative and cardiovascular diseases among others. As such, these connections have made the targeting of miRNAs attractive as a novel therapeutic strategy. Yet, to date, no miRNA-targeted drugs have yet been approved. The current state-of-the-art for targeting miRNAs relies on oligonucleotide-based approaches, such as anti-miRs or miRNA mimetics; however, many liabilities exist with these drugs, including hybridization-based off-target effects, toxicity, drug delivery problems and high cost. We are actively working to decipher new mechanisms by which to manipulate microRNA biology using small molecules for therapeutic applications.
Regulation of Cap-Dependent mRNA Translation:
In order to proliferate, evade cell death and promote angiogenesis and metastasis, cancer cells require an enhanced ability to produce protein products to perform these tasks, such as oncoproteins and growth and survival factors. The process by which this protein synthesis occurs is referred to as cap-dependent mRNA translation, as these transcripts contain a modified nucleotide, m7GpppX, at their 5’ terminus. Cap-dependent translation has been found to be dysregulated in many human cancers via mammalian target of rapamycin complex 1 (mTORC1)-mediated inactivation of 4E-BP1, a tumor suppressor and inhibitor of translation, or overexpression/activation of eIF4E, the 4E-BP1 protein binding partner and a known oncogene due its critical role in initiating translation by binding the m7GpppX cap of mRNA. Current therapeutic strategies under development for treating cancers with oncogenic translational signaling rely on allosteric or active site mTOR kinase inhibitors. Although rapamycin analogues have been approved for use in select cancers and results from active site mTOR inhibitor clinical trials have yet to be reported, a new strategy for combatting cancers with hyperactive mTOR signaling is warranted, particularly since drug resistance to these agents is a growing threat. Recent research has demonstrated that alteration of the complex cellular dynamics of the eIF4E-4E-BP1 protein-protein interaction (PPI) is a driver of cancer initiation, metastasis and mTOR inhibitor resistance; thus, we hypothesized that modulation of the eIF4E-4E-BP1 PPI is a druggable axis in mTOR-hyperactive drug-resistant and metastatic cancers. To investigate this hypothesis, we are taking several approaches including the rational design of eIF4E-targeted inhibitors, development of new screening assays and discovery of novel 4E-BP1 regulators using chemoproteomics.