New Chemical Tools for Advancing Lipid Metabolic Labeling

University Of Tennessee Knoxville, Knoxville TN

Investigators

Abstract

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professors Michael Best and Todd Reynolds from the University of Tennessee, Knoxville and their research groups are studying the development of chemical probes that enable detection, tracking, and imaging of the production of specific lipid molecules in cells. Lipids control many critical biological processes and therefore dysregulation of lipid biosynthesis results in severe diseases including cancer. Despite this significance, tracking the production and localization of lipids in cells remains challenging due to the complexity of membranes and the diversity of lipid structures that are constantly undergoing interconversion. Through this project, new strategies will be designed to overcome these longstanding obstacles by developing probes that infiltrate lipid biosynthesis to produce tagged versions of lipid products that facilitate their detection. This work will enable intensive training of researchers in an interdisciplinary environment that incorporates elements ranging from chemistry to biology. Additionally, participation in research will be broadened through outreach efforts aimed at enhancing understanding and enthusiasm for research among pre-collegiate students. In this project, probe analogues of lipid biosynthetic precursors bearing diminutive clickable tags are being developed to infiltrate normal cellular machinery and produce labeled lipid products. Post-derivatization of these molecules through bioorthogonal reactions is expected to enable the attachment of a variety of reporter tags that will facilitate tracking of lipid biosynthesis in cells. Distinct approaches are being undertaken to advance the approach of lipid metabolite labeling. On one hand, probes are being developed to enable labeling of specific and important lipid targets. In a complementary approach, probe strategies are being devised for labeling larger families of lipids to analyze lipid metabolism more broadly. In each of these cases, the goal is to synthesize new probe analogues of metabolic precursors and subject them to comprehensive evaluation of their labeling properties, including analysis of cellular labeling through fluorescence microscopy, validation of the identities of labeled lipids using multiple techniques, and determination of probe cytotoxicity. Furthermore, lipid metabolic labeling could be advanced by directing probes to specific cellular organelles using targeting moieties. This approach could provide new chemical tools for addressing important biological questions regarding the manner in which lipids are synthesized, trafficked, and dysregulated during crucial biological processes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.