MEOX1

Michael Alexanian joins Gladstone Institutes to discover new targets for treating and reversing heart failure SAN FRANCISCO, Sept. 1, 2022 /PRNewswire/ -- A healthy human heart is a powerful, pliable organ that expands and contracts rapidly to pump rich, oxygenated blood through the body. But for the millions of people around the world who have heart disease, this process goes awry. The heart becomes stiff, blocked or inflamed, and less efficient at pumping blood. In the United States alone, more than one of every 10 people have been diagnosed with heart disease. Continue Reading Michael Alexanian joins Gladstone Institutes to understand how genes are turned on or off in the heart of people with heart disease—and how drugs could reverse those changes and improve heart function. Photo: Michael Short/Gladstone Institutes Understanding how genes are turned on or off in the heart of people with heart disease—and how drugs could reverse those changes and improve heart function—is the research focus of Michael Alexanian (he/him), Ph.D., who is joining Gladstone Institutes as an assistant investigator. "We want to discover new therapeutic targets for treating and reversing heart failure," says Alexanian. "For a long time, scientists have focused on the role of muscle cells in heart failure and my lab is part of the movement to expand this focus to other cells in the heart, including fibroblasts, immune cells, and vascular cells." Over the past 5 years, as a postdoctoral scholar in the labs of former Gladstone investigator Saptarsi Haldar, MD, and of Gladstone President Deepak Srivastava, MD, Alexanian has already discovered gene programs related to heart fibrosis and inflammation. Now, he'll be launching his own lab at Gladstone to shed new light on the gene regulation processes leading to human diseases such as heart failure. "Michael is pioneering our understanding of how heart cells communicate in heart failure, one of today's most prevalent diseases," says Benoit Bruneau, Ph.D., director of the Gladstone Institute of Cardiovascular Disease. "With a deep molecular toolbox, he has already discovered important biology underpinning heart failure that could lead to new therapies." Getting to the Heart of Heart Cells Every cell in a person's body contains nearly identical sets of genes, providing the instructions for all the molecular programs the body needs to function. But each cell only follows a subset of these instructions at a time, because each cell contains specific regulatory molecules. These molecules interact with the cell's DNA and control which genes are turned on, or expressed. When someone's heart becomes diseased, the DNA inside their heart cells doesn't change, but the pattern of genes the heart cells express does. Scientists refer to this change as an epigenomic shift. Alexanian thinks that if he can describe this shift in new detail—as well as understand the regulatory molecules that trigger it—he'll be able to pinpoint ways to reverse it. To do so, he will leverage recent technology to probe gene expression in individual heart cells rather than in bulk heart tissue. "The advent of single-cell technologies gives us a way to capture the complexity of the heart," he says. "It's like opening a Pandora's box: once we begin to better understand the inner workings of the heart, we'll have all sorts of new ways of analyzing and targeting heart disease." His lab will focus on two specific changes that often happen in the heart with disease: fibrosis, or the stiffening and scarring of the heart following stress; and inflammation, the accumulation of immune cells and their secreted factors in the heart. He also wants to better understand the interplay between these two changes: how does chronic inflammation of the heart contribute to fibrosis? Answering this question has implications beyond heart disease, as other organs including the lungs and liver also develop fibrosis with disease. From Epigenomics and Stem Cells to Heart Disease Alexanian's interest in epigenomics was first piqued when he was an undergraduate at the University of Florence in Italy. He still remembers the first textbook chapter he read about gene regulation. "It struck me that the biological sophistication of different organisms wasn't related to the number of genes they had, but to these millions of layers of gene regulation," he says. "It really intrigued me and I decided that was what I wanted to study." After he graduated, Alexanian spent several months at the Walter and Eliza Hall Institute in Melbourne, Australia, working with epigenomics pioneer Marnie Blewitt, Ph.D.. Armed with enthusiasm, Alexanian returned to Europe for a graduate degree in stem cell biology at the University of Lausanne in Switzerland. He joined the lab of cardiovascular researcher Thierry Pedrazzini, Ph.D., to carry out studies on how genes were being regulated in stem cells. It was there that he became enamored with the heart. "My project was very focused on stem cell epigenomics," he recalls. "But I was surrounded by people talking about cardiovascular disease and I realized how important it was for society to tackle this disease." As a postdoctoral researcher at Gladstone, Alexanian merged these two interests—epigenomics and cardiovascular disease. In 2021, with colleagues in the Gladstone Institute of Cardiovascular Disease, he reported a master switch for heart fibrosis, MEOX1, responsible for altering levels of thousands of other genes. Now, Alexanian plans to follow up on that work with animal studies, showing how MEOX1 is affected by neighboring immune cells, and how targeting the MEOX1 gene could prevent or treat fibrosis of the heart and other organs. Inspired by Dinosaurs—and Improvisation Over the last decade, Alexanian has let his curiosity guide him from lab to lab around the world. Through it all, he has tried to pursue research that lets him think creatively. He says that biology often has a storytelling aspect that appeals to him. Indeed, he traces his love of science to the movie Jurassic Park, which he watched five times in the first 2 weeks it was being shown in Italian theaters. Then, with a group of elementary school friends, he pretended to isolate DNA from a mosquito trapped in amber. He never resurrected any ancient animals, of course, but the fun of experimentation stuck with him. For Alexanian, though, creative thinking isn't limited to his science. A long-time drummer and theater fan, he joined an improvisational acting group during graduate school in Lausanne. "I absolutely fell in love with improv," he says. "There's a lot of unappreciated technical preparation behind the scene, but then there's obviously this creative aspect on stage as well." In San Francisco, Alexanian couldn't find a comparable group—so he started one himself, founding "Improv at UCSF" to train scientists in improvisation. The class, which he teaches, is not only a fun outlet for scientists of all levels and disciplines but also a way to help them develop their leadership and communication skills. At Gladstone, Alexanian has found an outlet for his scientific creativity. He says the comradery and deep knowledge in both epigenomics and cardiovascular science make it feel like the right place to launch his lab. "The most effective way to do science is by really using the environment and experts around you to your advantage," he says. "Gladstone is a place that makes it very easy to do this." About Michael Alexanian Michael Alexanian, Ph.D., is an assistant investigator at Gladstone Institutes and an assistant professor in pediatrics at UC San Francisco. Alexanian received his bachelor's and Master's degrees from the University of Florence in Italy. After he graduated, Alexanian spent several months at the Walter and Eliza Hall Institute in Melbourne, Australia, working with epigenomics expert Marnie Blewitt. Alexanian returned to Europe for a graduate degree in stem cell biology at the University of Lausanne in Switzerland in the lab of Thierry Pedrazzini. During his doctoral studies, he investigated the role of non-coding RNAs, including transcribed enhancers and long non-coding RNAs, in pluripotency and early cell fate specification. During his postdoctoral work at Gladstone under the supervision of Deepak Srivastava and Saptarsi Haldar, Alexanian discovered gene programs related to cellular plasticity in the context of heart failure. About Gladstone Institutes To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco. Media Contact: Julie Langelier | Associate Director, Communications | [email protected] | 415.734.5000 1650 Owens Street, San Francisco, CA 94158 | gladstone.org | @GladstoneInst SOURCE Gladstone Institutes

SAN FRANCISCO, June 23, 2021 /PRNewswire/ -- A healthy heart is a pliable, ever-moving organ. But under stress—from injury, cardiovascular disease, or aging—the heart thickens and stiffens in a process known as fibrosis, which involves diffuse scar-like tissue. Slowing or stopping fibrosis to treat and prevent heart failure has long been a goal of cardiologists. Now, researchers at Gladstone Institutes have discovered a master switch for fibrosis in the heart. When the heart is under stress, they found, the gene MEOX1 is turned on in cells called fibroblasts, spurring fibrosis. Their new study, published in the journal Nature, suggests that blocking this gene could prevent fibrosis in the heart—and other organs that can similarly fail from stiffening over time. "With these findings, we may have an entirely new way to stop that slow but steady progression of heart failure that affects 24 million people worldwide," says Deepak Srivastava, MD, president and senior investigator at Gladstone and senior author of the study. "Right now, we don't have any drugs that effectively prevent fibrosis." Fibroblasts are key to normal organ repair and integrity; they're the most abundant cell in connective tissue and congregate at sites of bodily damage or disease. In many cases, their presence is beneficial. They help launch immune responses, mediate inflammation, and rebuild tissue. But in chronic disease, activated fibroblasts can continuously create scar tissue, impeding normal organ function. Researchers knew that in mice with heart disease, blocking a class of proteins known as BET proteins slowed fibrosis and improved heart function, although it wasn't clear which cell type in the heart was being affected. They also knew that BET proteins are needed throughout the body for many important functions, including normal immunity. "To treat a heart failure patient with a BET inhibitor is a sledgehammer approach, because we might prevent fibrosis, but we'd likely also disrupt many other critical cellular functions throughout the body in the process," says Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). "Our hope was that if we could understand the precise mechanism through which BET works in the heart, we could home in on a narrower target with fewer side effects." Srivastava's group studied mice who developed heart failure, and treated them daily with a BET inhibitor for 1 month. The researchers used single-cell RNA sequencing and single-cell epigenomics—which can reveal which genes in a cell are accessible and being turned on at any given time—to compare heart cells from mice before, during, and after the treatment, and correlate those results with heart function. These technologies allowed the researchers to analyze thousands of cells at once, and separate them based on their specific cell type. Thanks to a close collaboration with the laboratory of Katie Pollard, PhD, at Gladstone, they developed new computational methods to learn from the vast amount of data generated by their analysis. While the scientists didn't find significant changes to heart muscle cells, they observed that the treatment induced striking changes in cardiac fibroblasts, which represent more than half the cells in the human heart. In particular, the researchers discovered that the gene MEOX1 was highly active in the mice with heart failure and that its levels dramatically dropped when the mice were treated with the BET inhibitor. Moreover, the levels of MEOX1 correlated with activation of the fibroblasts; when the gene was switched on, the fibroblasts were better at making scar tissue. In fact, MEOX1 seemed to be a "master regulator" of fibroblast activation, controlling thousands of other genes that contribute to fibrosis. "MEOX1 is a gene known to be important in early development, but not much was known about it in adult disease, so our findings were quite surprising," says Michael Alexanian, PhD, a Gladstone postdoctoral scholar and first author of the new study. The findings point to the precise part of the DNA, regulated by BET, that is responsible for MEOX1 to be turned on in disease states. Using CRISPR genome-editing technology, the scientists showed that deleting this small part of the DNA prevented MEOX1 from being activated, even under stress. The team went on to show that blocking MEOX1 from being switched on had the same effects as a BET inhibitor—it blocks the activation of fibroblasts. The researchers also studied other organs that commonly become fibrotic with disease, and found that cellular stress led to higher levels of MEOX1 in human lung, liver, and kidney fibroblasts. "Fibrosis is much broader than just the heart; it affects many other organs," says Srivastava. "We hope this discovery provides an avenue to slow down or stop fibrosis in many settings." More studies are needed to show whether blocking MEOX1 could have therapeutic value in humans. Srivastava and his colleagues are now conducting additional studies to better understand the long-term role of MEOX1 in heart disease and heart failure. "In a coordinated effort to design novel therapies for heart failure, researchers are looking for molecular clues to use as therapeutic targets," says Bishow Adhikari, PhD, a program officer in the heart failure and arrhythmias branch, located within the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute. "These findings are highly informative and bring researchers closer to advancing new therapeutic strategies to better predict and treat heart disease." About the Study The paper "A Transcriptional Switch Governs Fibroblast Activation in Heart Disease" was published by the journal Nature on June 23, 2021. Other authors are: Pawel Przytycki, Arun Padmanabhan, Lin Ye, Bárbara Gonzàlez Teràn, Ana Catarina Silva, Qiming Duan, Sanjeev Ranade, Franco Felix, Clara Yougna Lee, Nandhini Sadagopan, Angelo Pelonero, Yu Huang, Casey Gifford, and Saptarsi Haldar of Gladstone; Rudi Micheletti and Michael Rosenfeld of UC San Diego; Joshua Travers and Timothy McKinsey of University of Colorado; Ricardo Linares-Saldana, Li Li and Rajan Jain of University of Pennsylvania; and Gaia Andreoletti of UCSF. The work at Gladstone was supported by the Swiss National Science Foundation, the National Institutes of Health (P01 HL098707, HL098179, R01 HL127240, P01 HL146366, R01 HL057181, R01 HL015100, C06 RR018928), the San Simeon Fund, the Tobacco–Related Disease Research Program, A.P. Giannini Foundation, Michael Antonov Charitable Foundation Inc., Sarnoff Cardiovascular Research Foundation, the American Heart Association, the Roddenberry Foundation, the L.K. Whittier Foundation, Dario and Irina Sattui, and the Younger Family Fund. About Gladstone Institutes To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco. Media Contact: Julie Langelier | Associate Director, Communications | julie.langelier@gladstone.org | 415.734.5000 1650 Owens Street, San Francisco, CA 94158 | gladstone.org | @GladstoneInst