Introduction- Cardiovascular Disease
Anita M -
Hello! My name is Anita and my senior research project is on the effects of UPR Regulator ATF6 on the expression levels of ER Transmembrane Protein GRASP55 in cardiovascular disease.
Your heart works from before your first breath to well after your last. This vital muscle works tirelessly to keep blood flowing throughout your body. Yet, every year more and more people- -young children, high performance athletes, seniors– become diagnosed with cardiovascular disease.
Cardiovascular disease is the #1 cause of death in the United States and includes a variety of conditions ranging from atherosclerosis (build-up of plaque in the coronary arteries) to cardiomyopathy (damaged heart muscle tissue) to myocardial infarctions (also known as heart attacks, where blood flow to the heart is stopped). This project focuses primarily on heart attacks.
The American Heart Association estimates that every 40 seconds, somebody in the U.S. experiences a heart attack, meaning around 800,000 people experience one every year. Assuming somebody survives a heart attack, they will experience short-term and long-term effects. The short-term effects include inflammation of undamaged heart tissue, while the long-term effects are eventual heart failure due to hypertrophic cardiac tissue growth.
So how can we prevent this?
As the heart recovers from the heart attack, protein demand increases in heart cells, causing Endoplasmic Reticulum (ER) stress to the cells. This ER stress can lead to the formation of misfolded protein aggregates, which causes proteotoxicity and interferes with normal cellular behavior.
Scientists have discovered a molecule called Activating Transcription Factor-6 (ATF6) that, when activated, helps maintain the balance of proteins and prevents protein aggregates from forming. It does this by activating the unfolded protein response (UPR), a cell response that essentially gets rid of any non-functional proteins. By doing so, ATF6 maintains the cell’s balance of proteins (proteostasis). Drug 147 is a newly developed drug that activates ATF6.
Golgi Reassembly Stacking Protein of 55 kD (GRASP55) is another part of the cell that helps maintain proteostasis. GRASP55 gets rid of misfolded protein aggregates by secreting them out of the cell. In fact, secretion of protein aggregates is dependent on GRASP55, making GRASP55 play a vital role in maintaining proteostasis.
Both ATF6 and GRASP55 control proteostasis through different mechanisms. Since drug 147 has recently been developed, its effects on other pathways within the cell are unknown. The aim of my project is to investigate how activating ATF6 through drug 147 affects the expression of GRASP55. Altering GRASP55 expression could affect the secretion of misfolded protein aggregates, which could affect proteostasis. Throwing off proteostasis causes more ER Stress on the cell, leading to an increased chance of heart failure for the patient, which we want to avoid.
I am thrilled to have the opportunity to work at the Translational Cardiovascular Research Center to conduct this research and help heal our world from cardiovascular disease. In the next few weeks, I’ll be training to learn various lab procedures, like cell cultures and immunoblots. Stay tuned for more updates!