Undergraduate Research in the Butterfield Laboratory

Do undergraduates make critical contributions to cutting-edge research? The answer is a decidedly yes, and not in small numbers.  Professor D. Allan Butterfield has matriculated more than 160 undergraduates in his laboratory over the 43 years he has been at UK.  Nearly all of these undergraduate researchers performed independent research under the aegis of CHE 395, “Independent Research in Chemistry.”  Approximately 60-plus refereed scientific papers have resulted from the work of these undergraduates [nearly 10 percent of Prof. Butterfield’s total publications (H-index = 96)].  This current spring 2018 semester, four CHE 395 students are in Prof. Butterfield’s laboratory.  The following is a brief synopsis of their research, their thoughts about their education at UK, and their future plans. 

       Angela Hinchie and Eric Vogt are collaborating on investigations of mTOR (mammalian target of rapamycin) in brains of a unique rat model of inherited Parkinson disease with support from a NIH grant held by Prof. Butterfield. mTOR is a multi-protein complex that normally is quiescent.  Upon activation by a number of stimuli, including amyloid beta-peptide that accumulates in brains of persons with Alzheimer disease, the brain loses its ability to remove cellular debris by the process known as autophagy, and the brain experiences insulin resistance.  Both inhibition of autophagy and insulin signaling following activation of mTOR are highly damaging to neurons and lead to their death.  Prof. Butterfield previously used immunochemical approaches to dissect the PI3K/Akt pathway leading to activation of mTOR in brains of Alzheimer disease and its earlier stages with support of a different NIH grant.  Angela and Eric are testing the hypothesis that mTOR is activated in brain as a function of age of a rat model of Parkinson disease. PINK1 is a mitochondrial kinase that serves to monitor damage to mitochondria, the powerhouses of cells.  Upon damage, PINK1 phosphorylates a key protein that starts a pathway leading to degradation of mitochondria, thereby preventing excess leakage of damaging superoxide free radicals.

       Mutations in the gene for PINK1 are known to cause inherited Parkinson disease.  A rat has been produced in which the gene for PINK1 has been deleted (the ultimate mutation is complete loss of the gene), and Prof. Butterfield is testing the fidelity of this rat as a model of inherited Parkinson disease.  Angela and Eric examined multiple components of the mTOR activation pathway using antibodies directed against the phosphorylated and non-phosphorylated forms of each protein component of the pathway in brains of PINK1 knockout rats obtained at 2,4, 6, and 8 months.  The results are consistent with the idea that the mTOR pathway is activated with age of the PINK1 KO rat.  More studies need to be completed, but Prof. Butterfield is confident that at least one refereed scientific paper will result from their studies with both Angela Hinchie and Eric Vogt as co-authors, a remarkable achievement for these talented undergraduates.

Angela Hinchie reflects on her time at UK and her next position: “The focus on undergraduate research at the University of Kentucky through the CHE 395 classes has been extremely helpful for me, both in growing as a student, and figuring out my future plans. The chemistry department at UK has extensive resources for research and many professors who are excited to mentor undergraduates. Working with Dr. Butterfield for the past year has been an incredible experience. He has done amazing work through the university and with collaborators around the world, resulting in many exciting findings in Alzheimer disease. He definitely expects a lot out of everyone in the lab, and pushes us to succeed. I have learned a lot from this lab and his mentorship, and I’ll miss working here after graduation this May. After I graduate, I will attend the University of Pittsburgh’s Interdisciplinary Biomedical Graduate program to obtain my PhD, and continue with a research career.”  Eric Vogt also reflects on his time at UK and future plans: “Doing this research at the University of Kentucky has been tremendously helpful. The faculty here have been incredibly supportive of our research, and have been great about making us feel at home. Being able to do this research under Dr. Butterfield with his vast background in neurodegenerative diseases is something that I have found is unique to the University of Kentucky. In doing research here at UK I have gained insights and gotten experience that will aid me in future endeavors. At this moment my future is one of waiting. I am wait-listed at both the University of Kentucky College of Medicine and the University of Louisville Medical School. I ultimately plan to complete medical school and practice medicine as a primary care physician.”

Nicole Martin is performing CHE 395 under Prof. Butterfield’s supervision in the laboratory of one of his collaborators, Prof. Elizabeth Head, in the Sanders-Brown Center on Aging.  Nicole is investigating the activity of a key glycolytic enzyme, alpha-enolase, in the brains of young to elderly persons with Down syndrome.  The great majority of Down syndrome persons, between 40-50 years of age, develop Alzheimer disease pathology and dementia. Prof. Butterfield had published earlier that alpha-enolase is an oxidatively modified enzyme in brains of Alzheimer disease and one of its earlier stages, amnestic mild cognitive impairment, i.e., before dementia, and conceivably could be involved in the progression of this disorder.  Butterfield also showed earlier using redox proteomics that in brains from Down syndrome alpha-enolase is covalently bound by the oxidative stress marker, HNE, a reactive aldehyde product of lipid peroxidation that forms covalent bonds to cysteine, histidine, and lysine residues of proteins by Michael addition. This process changes the conformation and causes dysfunction of the enzyme.   Nicole is using an assay kit to examine the activity of HNE-modified alpha-enolase in brains from Down syndrome persons as a function of age.  Upon completion of her research, Nicole will know if alpha-enolase is dysfunctional in brain throughout the progression of Down syndrome to Down syndrome with Alzheimer disease.  If successful, this research will provide insights into both Down syndrome and Alzheimer disease and will lead to a refereed scientific communication.     

Nicole Martin reflects on her time at UK and her next position: “The University of Kentucky and the Chemistry Department have prepared me for my future endeavors, as upon graduation I will be attending the University of Kentucky College of Medicine this Fall. I have been extremely lucky to have been surrounded encouraging professors and exceptional peers who have brought me to this step. I have received so much support that has caused me to grow intellectually, and my four years as an undergraduate here have definitely shaped me into the person I am today.”

Brad Seahorn is performing literature-based CHE 395 research in Prof. Butterfield’s laboratory.  Supported by a third NIH grant, Prof. Butterfield is testing whether his hypothesis of the mechanisms of chemotherapy induced cognitive impairment (CICI) are correct.  Prof. Butterfield has published extensively on how free radical generating chemotherapeutic agents, that themselves cannot cross the blood brain barrier, lead to oxidative damage and mitochondrial dysfunction and subsequent neuronal death.   Brad is researching all of Prof. Butterfield’s papers and the existing literature to develop ideas of the next set of studies related to CICI that Prof. Butterfield might wish to consider.  Though not laboratory-based research, his research is increasing Brad’s ability to assess the scientific literature and how to go beyond established facts to suggest new studies.   Brad Seahorn states: “Following graduation in May 2018, I plan to enter the work force in the field of analytical chemistry.”

Professor Butterfield indicates that “the undergraduate students I have had and currently have in my laboratory almost universally are bright, hard-working, and highly disciplined in their approach to research.”  He further states, “Essentially each person who matriculated through my laboratory has gone on to Ph.D. programs, professional schools, the workforce, or the military.”  He indicated that “it has been my great privilege to be the supervisor and mentor of my current and prior CHE 395 students, and I am grateful to the UK Department of Chemistry for supporting undergraduate research.”  

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