CDI-Type II: Discovery of Biophysical Mechanisms Inducing Signaling and Cytotoxicity: An Experimental Approach Enabled by Cyber Tools

Michigan State University, East Lansing MI

Investigators

Abstract

PI: Christina Chan, Michael Feig and Amadeu Sum Institution: Michigan State University Proposal Number: 0941055 Intellectual Merit. This project aims to integrate molecular biology, biophysics, and cellular studies with molecular modeling to provide a transformative understanding of complex biological systems comprised of multiple interacting processes. Specifically for this project the PIs plan to study the endoplasmic reticulum transmembrane protein kinase/endoribonuclease (IRE1), which is activated in response to the Unfolded Protein Response (UPR). This has broad implications on a number of diseases, since UPR is known to be activated in cancers, viral infection and many other diseases. This study is a first at developing a multi-scale model to integrate the various domains of the transmembrane protein to understand how palmitate activates the protein, representing an innovative, multi-scale approach to gather, process, and interpret data from the molecular to the cellular level. Among the fatty acids, saturated fatty acids, i.e., palmi-tate, are typically the most cytotoxic. Saturated fatty acids have been shown to cause cell death in many types of cells and be risk factors associated with a variety of diseases. Transformation/Innovation. This project will provide much needed insight into the general understanding of transmembrane protein kinases. The findings of will rely on computational analysis of biophysical events as well as integrating tools from biology, chemistry, physics, and engineering. This approach will provide insight that will complement and aid in the interpretation and analysis of macroscopic measurements of cellular function, signaling and toxicity, and eventual design of strategies to control or prevent cell damage and modulate cell signaling induced by fatty acids. The computational and experimental approaches rely on the findings at the molecular levels, through a combination of molecular modeling and molecular biology, to drive the bio-chemical and signaling transduction studies. While the biochemical and signaling studies of the cellular responses are necessary, the complexity of cellular processes hinders a clear interpretation and understanding of the experimental results. As such, design and engineering of these studies will be driven by computational findings of the molecular processes. This approach represents a cyber enabled methodology for a rational investigation of the biophysical effects of fatty acids on cells. Therefore, this study has implications on how saturated fatty acids may be involved in multiple diseases as well as on the efficacy of current drug therapies that are targeted to inhibit transmembrane kinases. Broader Impact. The studies pursued here are centered on biophysical interactions with membranes and proteins as one of the underlying mechanisms behind palmitate-induced alterations in cellular function leading to cytotoxicity or death of cells. The application of bio-physical concepts to this problem is a novel approach that has been largely overlooked in favor of biochemical and signaling processes. From an educational standpoint, this project will provide a broad exposure to the students with an opportunity to integrate the knowledge base from vastly differing fields and to apply quantitative tools to investigate non-traditional engineering problems. The PIs have supported both (female and minority) high school and undergraduate students in the laboratory. The PIs will continue to enlist the help of high school and undergraduate students to obtain preliminary results during the summer months. The undergraduate and high school students provide an opportunity for the graduate students in the lab to gain supervisory experience along with their traditional research experience. For the high school and undergraduate students, the goal is to encourage them to pursue careers in engineering and science by exposing them to hands-on laboratory research experiences. The PIs have and will continue to develop new courses that incorporate the research development and findings. The methodology developed will be disseminated through the web, in addition to traditional modes, such as oral presentations at scientific meetings and publications in scholarly journals.