Research

Research in the Kenealey lab covers a wide variety of fields and topics from cancer research to protein biochemistry, but they are all held together by the underlying theme of natural product bioactivity: how are these naturally occurring chemical compounds synthesized, and how do they interact with the human body?

These are some of our current projects.


Resveratrol and Calcium Signalling in Cancer Cell Lines

As far back as ancient Mesopotamia, the health benefits of grapes have been well known. Part of this can be attributed to the natural compound resveratrol, which is found in the skin of muscadine grapes (Vitis rotundifolia). Resveratrol has been implicated in several of the health-related benefits of wine, including a decreased risk of heart disease and cancer.

Our work focuses on defining the biochmical mechanism by which resveratrol attacks and kills cancer cells. PMCA is a calcium ion pump located in the cell membrane, and research indicates that PMCA knockdown or inhibition by resveratrol leads to Ca2+ buildup inside the plasma membrane, and eventually induction of the apoptotic pathway, or programmed cell death. Our work focuses on defining the biochemical mechanism by which resveratrol inhibits PMCA in cancer cell lines.

 

Relevant Publications

Kenealey JD, Subramanian L, Van Ginkel PR, Darjatmoko S, Lindstrom MJ, Ghosh SK, Song Z, Hsung RP, Kwon GS, Eliceiri KW, et al. Resveratrol Metabolites Do Not Elicit Early Pro-apoptotic Mechanisms in Neuroblastoma Cells. J Agric Food Chem. 2011;59(9):4979-4986.

 


The Impact of Resveratrol on Cancer at the Transcriptome Level

Resveratrol (a compound described in the project “Resveratrol and Calcium in Cancer Cell Lines”) has gained significant popularity in recent years by demonstrating toxicity towards cancer cells while leaving regular, healthy cells relatively unharmed. While promising in future chemotherapeutic therapies, little is known about the precise mechanism through which resveratrol manages this unique effect. The purpose of this analysis is to pinpoint more specifically the genes and biochemical pathways that are most greatly impacted by resveratrol, which could lead to a better understanding of how to utilize this compound in nontoxic chemotherapeutics.
Through performing RNA Sequencing on cancer cells with and without resveratrol treatment, we can gain a clearer picture of how resveratrol impacts the transcriptome of cancer cells. In essence, we are taking a snapshot of the entire inner workings of cancer cells – and seeing the changes that occur when resveratrol is added. By comparing the two “snapshots,” we can see the all-encompassing impact of resveratrol on cancer cells, indicating areas of interest and further study. Such results could bring about groundbreaking discoveries on the mechanisms of resveratrol in killing cancer cells, giving scientists a better idea of how to make use of this extremely healthy compound.

 


Characterizing Soluble Fiber Biosynthesis in Oat

This is a project we are doing in collaboration with the Orphaned Crops Lab at BYU. Oats are a crop plant with demonstrated nutritional benefits, including an increased resistance against heart disease. One of the major contributors to cardiovascular health in oats is the high levels of (1,3)(1,4) mixed-linkage β-D-glucans, a type of polysaccharide similar to cellulose but with a few minor differences that give it valuable bioactivity.

CslF6 (Cellulose synthase-like) is a transmembrane protein that catalyzes the biosynthesis and deposition of β-D-glucans in the oat grain. The Jellen lab recently sequenced the gene for this enzyme and we are now working together on characterizing the catalytic activity and reaction kinetics of the gene product enzyme.

 


Michaelis Collaboration

Dr. Michaelis taught my o-chem class.

 

 

 

 

 


Avenanthramides and Cell-free Protein Expression

Another part of our collaboration with the Orphaned Crops Lab deals with a unique metabolite produced by oats: avenanthramides. These are relatively simple compounds, but have been shown to defend the body against inflammation, heart disease, and cancer. They are found only in the oat species and are causal to many of the folk medicinal properties of oat. Avenanthramides are produced as a branch-off of the aromatic amino acid biosynthesis pathway, and research indicates that they play a role in plant defense against microbial attack.

Cell-free protein and metabolite expression systems (as opposed to in vivo expression) also present excellent opportunities for protein and metabolic engineering due to their ease of use, customizability, and efficiency. Currently, cell-free systems made from cell extracts of E. coli, wheat germ, and rabbit reticulocyte are among the most well established and popular, but they have important shortcomings such as the difficulty of adding post-translational modifications to proteins expressed.

Our goal is twofold: We want to clarify the biosynthetic process for avenanthramides, and then synthesize them via a metabolic engineering approach in a brand new cell-free system that we are developing from oat cells. In doing so, we hope to make avenanthramide nutritional supplements more cost effective and accessible to the public, as well as create a new cell-free system that could address some of the shortcomings of those already in use.