Title

Reprogramming Transcription Factors to Study Addiction [online video]

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Original Publication Date

2021

Document Type

Presentation

Comments

7th Annual VCU 3MT® Competition, held on October 15, 2021.

Abstract

This research concerns the use of CRISPR-based techniques to mimic the activation that occurs with cocaine use, but limit it to individual transcription factors so that they can be studied in the context of drug addiction and determine their causal relationships in driving drug response.

Transcription

Joseph Picone: Cocaine abuse disorder continues to be a major health issue, with overdose deaths rising sharply since 2016. Overdose is usually the end result of a vicious cycle where victims require ever-increasing dosage to elicit the same high. Now, why is it that drugs like cocaine become less rewarding, requiring more to get the same high? The answer is tolerance. But what are the molecular mechanisms that could be driving tolerance? That is what my project seeks to answer. Tolerance is the result of epigenetic changes in the brain, with altering gene expression without changing the underlying genetic code. If you think of the genome as a cookbook and genes as recipes, then epigenetics would determine what pages the book is open to. Without seeing the instructions, a recipe can't be made. Therefore, you can influence what's being cooked by changing what pages are accessible. And so transcription factors are the driving factors in this process, interacting directly with DNA and influencing its accessibility. These epigenetic mechanisms are what allow neurons to adapt and change and result, or, facilitate processes of learning and memory. Unfortunately, it's these same processes that can be hijacked by drugs of abuse, like cocaine, to induce detrimental changes. So when someone uses cocaine, it causes changes to the chemical signaling in their brain, resulting in a psychoactive effect making them high. But beyond just this high, the change in chemical transmission signals to transcription factors to shift the neuron into a tolerance state, so that the next time the individual uses cocaine, it won't have that same kick, requiring them to do more and starting the cycle over again at higher and higher doses. I study the transcription factors that drive this cycle by identifying and manipulating them. The tricky part is determining the causal role of specific transcription factors, as there are thousands of them expressed with cocaine use. And since these transcription factors facilitate learning and memory, we want to use a scalpel and not a sledgehammer in our approach. Luckily, cutting edge CRISPR-based techniques allow me to mimic the activation that occurs with cocaine use, but limit it to individual transcription factors so that I can study them in the context of drug addiction and determine their causal relationships in driving drug response. One of these factors known as CFP 189 has already appeared to be significant for driving cocaine tolerance. By surgically delivering a CRISPR tool capable of activating CFP 189 in the brains of mice, I can induce a tolerant state even prior to cocaine exposure. This is significant because it shows that activation of just one transcription factor can be sufficient to drive tolerance. And it is my hope that these, my study can be done, can be used to uncover potential targets for anti-addiction medications which could help end the cycle of addiction. Thank you.

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