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Arty_Cells.jpg

Research


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Research



Overview

Cell death is a fundamental biological process necessary for development and to maintain homeostasis in adulthood. When the normal regulation of cell death is lost this can cause diseases such as cancer. From a medical perspective, it is often the goal of various treatments to induce cell death (e.g. chemotherapy or radiation treatment for cancer), or to prevent cell death when it is not wanted (e.g. during stroke or heart attack). Understanding the biochemical and genetic regulation of cell death therefore has substantial basic and clinical importance.

Emerging evidence suggests that cell death comes in many 'flavors'. In the 1970's the first regulated form of cell death was identified: apoptosis. Since then, it has become clear that a cell can die due to the activation of several biochemically and genetically distinct 'non-apoptotic' pathways. These pathways do not involve activation of caspases or result in the typical morphological characteristics seen in dying, apoptotic cells. As a postdoctoral fellow, Scott spearheaded the discovery of one such pathway, termed ferroptosis. This process can be triggered when the normal uptake and metabolism of the amino acid cysteine is perturbed. Evidence suggests that this pathway may be activated during pathological cell death in the kidney, heart, brain and other tissues. It may also be possible (and possibly useful!) to trigger ferroptosis in cancer cells, especially those that are not sensitive to undergoing apoptosis.

In the Dixon lab we have a broad interest in the regulation of non-apoptotic and apoptotic cell death. In particular, we want to understand how the perturbation of intracellular metabolism leads or contributes to different forms of cell death.  This work may have important clinical applications if we can find new drugs that can activate or inhibit different forms of cell death in a way that is helpful to treat diseases such as cancer (insufficient cell death) or neurodegeneration (too much cell death). We also have a strong interest in developing new technologies to monitor and quantify cell death.

We are currently pursuing studies in two general project areas (outlined below). New graduate students and postdocs candidates with interests in these areas should contact Scott. He likes to talk about cell death, a lot.
 

Project 1. Large-Scale Analysis of Cell Death Kinetics
We are developing new ways to analyze cell death and, in particular, the kinetics of cell death. One approach, called scalable time-lapse analysis of cell death kinetics (STACK) uses reporters of live and dead cells combined with high-throughput, live-cell imaging and mathematical modeling to describe the timing of cell death onset and the maximal rate that this process occurs in a population. We are currently using this technology to analyze the kinetics of cell death for various classes of lethal compounds, investigate how cell death kinetics are altered by compound interactions and discover novel lethal perturbations with unique cell death kinetics.

Future goals include:

  • Integration of cell death kinetics with morphological attributes of dying cells to identify and classify new lethal molecules and pathways
  • Characterizing cell death kinetics in response to combinations of two or more lethal molecules
  • Applying this technology at the single-cell level to investigate the heterogeneity of cell death within isogenic populations
  • Further developing this technology for applications with primary cells or tissue samples

Project 2. Analysis of Non-Apoptotic Cell Death
We currently have several project on-going that are investigating the regulation of ferroptosis and other forms of non-apoptotic cell death at the cellular and molecular levels.

Specific questions we are trying to address include:

  • How does erastin inhibits system xc- at the molecular level?
  • How are glutathione levels governed within the cell?
  • How is ferroptosis regulated by other signaling and metabolic pathways?
  • Could other molecules exist that induce other, novel non-apoptotic cell death pathways?