Arty_Cells.jpg
Arty_Cells.jpg

Research


SCROLL DOWN

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. In medicine, the goal of various treatments is often 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.

In the 1970's the first regulated form of cell death was identified: apoptosis. A big recent surprise is that, in addition to apoptosis, cells can die through the activation of other biochemically and genetically distinct 'non-apoptotic' pathways. These pathways do not involve activation of caspases or result in the typical morphological characteristics seen in 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 currently 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 three 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?
  • How does lipid metabolism regulate this process? 
Pathway_3.png

Project 3. Investigating the Role of Protein Palmitoylation in Cell Death
Building off of our interests and expertise in lipid biology, we have become curious about the role of protein S-palmitoylation (i.e. the modification of proteins with the saturated fatty acid palmitate) in apoptotic and non-apoptotic cell death. We previously identified a palmitoyl acyltransferase that was essential for non-apoptotic cell death and we continue to characterize the role of this enzyme in that process.