This project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences and the Cellular Dynamics and Function Cluster in the Division of Molecular and Cellular Biosciences.
Calcitriol is a form of Vitamin D that provides an important control mechanism for many processes including proper bone growth, immune function, metabolism (the chemical reactions of life), and blood pressure. Calcitriol has been shown to inhibit a signaling mechanism that is responsible for correct embryonic development, but this inhibition appears to involve a novel mechanism distinct from the well-known vitamin D receptor. This project will identify the mechanisms through which Vitamin D-based compounds regulate signaling mechanisms as a first step to understanding their larger role in embryonic development. A new undergraduate course for non-scientists, "Molecules in the Media," will incorporate the project findings in the context of understanding Vitamin D as a natural hormone. Outreach with a local high school will provide unique opportunities to explore advanced techniques and instrumentation not typically available in high schools.
The recent identification of Vitamin D-based seco-steroids as potent inhibitors of Hh signaling and mammalian development represents an exciting new avenue of research for this class of endogenous regulators. The physiological activity of these compounds is traditionally attributed to the direct binding of calcitriol to VDR and subsequent activation of a canonical VDR signaling cascade; however, there is an increasing amount of evidence to suggest that this is a simplified description of endogenous Vitamin D signaling. Specifically, the anti-Hh effects of several structurally related Vitamin D-based seco-steroids are not regulated via VDR or Smoothened (Smo), a 7-transmembrane GPCR-like receptor that is a key Hh pathway component and the initially described target of calcitriol. The overall goal of this project is to study cellular signaling during mammalian embryogenesis by utilizing a series of direct target identification approaches to fully identify cellular proteins that mediate inhibition of the Hh signaling pathway by Vitamin D-based structures. To accomplish this goal, a series of Vitamin D structures incorporating a defined label (alkyne, biotin, or fluorescent) will be synthesized and utilized as chemical probes to explore global binding interactions between Vitamin D and the cellular proteome.
