PCAPIP · Towards understanding non-canonical phosphatidylinositol kinases in the maintenance of prostate metabolism.

As a result of it’s specialized secretory functions, the prostate has a unique biology that makes it prone to the development of cancer. Specifically, a strong dependence on hormonal stimulation through the androgen receptor (AR) pathway that is implicated in driving downstream changes to the central metabolism of the cell. To find answers to clinical questions, I am delving into the fundamental mechanisms of a previously overlooked family of lipid kinases. The type II phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) are responsible for regulating a proportion of phospholipid species found embedded in the membranes of various cellular organelles. Intricate differences of the composition of these membranes can have a major effect on the regulation of cell cycle, metabolite trafficking, growth and survival. Herein, I outline a basic examination of the PI5P4Ks that will establish the first understanding of their phenotypic importance in prostate cells. There is reason to believe that these enzymes are critical regulators of the AR pathway that may be a trafficking conduit for changes to AR regulated metabolites. To test this, I am generating the first prostate-specific PI5P4K knock-out mouse model. A state-of-the-art metabolomic evaluation of both this animal model and a collection of human cell models will uncover the ultimate relevance of the PI5P4Ks in prostate biology. The proposed study will provide valuable insights into a non-canonical family of kinases that could lay the groundwork their development as novel drug targets.