Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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Hanjoong Jo

Flowing toward potential CV therapeutic

It’s not a blockbuster cardiovascular drug – yet. But the pathway from bench to bedside is easy to see.

In a recent eLife paper, Hanjoong Jo’s lab characterizes a “flow-kine”: a protein produced by endothelial cells in response to healthy blood flow patterns. Unlike other atherosclerosis-linked factors previously identified by Jo’s team, this one – called KLK10 — is secreted. That means that the KLK10 protein could morph into a therapeutic.

Hanjoong Jo, PhD

We can compare KLK10 to PCSK9 inhibitors, which lower LDL cholesterol and have a proven ability to prevent cardiovascular events. KLK10 acts in a different way, not affecting cholesterol, but instead inhibiting inflammation in endothelial cells. KLK10 can protect against atherosclerosis in animal models, when delivered by injection.

“The most important clinical implication is that we were able to see that human atherosclerotic plaques have a low level of KLK10,” Jo says. “In a healthy heart, the expression level is OK.”

Jo sees similarities between KLK10 and myokines, exercise-induced proteins secreted by skeletal muscle cells. Looking ahead, his lab has begun experiments testing how exercise affects KLK10 and other protective factors.

Jo and his colleagues are in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Using a workhorse model of disturbed blood flow in atherosclerosis, his team has steadily identified a stream of genes involved in the disease process. KLK10 is one of several down-regulated by disturbed blood flow.

Jo cites the transcription factor KLF2 as another good example of a protective protein identified by his team’s approach. KLF2 has a similar protective function, but it is expressed inside endothelial cells and stays inside the cell. KLK10 is secreted into the circulation, giving it more obvious therapeutic potential.

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Posted on February 14, 2022 by Quinn Eastman in Heart Leave a comment

Dissecting atherosclerosis at the single cell level: tasting each piece of a fruit salad

More than a decade ago, Hanjoong Jo and colleagues developed an elegant animal model allowing the dissection of atherosclerosis. It was the first to definitively show that disturbed patterns of blood flow determine where atherosclerotic plaques will later appear.

In atherosclerosis, arterial walls thicken and harden because of a gradual build-up of lipids, cholesterol and white blood cells, which occurs over the course of years in humans. The Jo lab’s model involves restricting blood flow in the carotid artery of mice, which are fed a high-fat diet and also have mutations in a gene (ApoE) involved in processing fat and cholesterol. The physical intervention causes atherosclerosis to appear within a couple weeks. Inflammation in endothelial cells, which line blood vessels, is visible within 48 hours.

The shear-sensitive gene LMO4 is turned on in the middle boxed region, but not the other two, because of disturbed flow in that area of the aorta

Now Jo’s lab has combined the model with recently developed techniques that permit scientists to see molecular changes in single cells. The results were published Tuesday in Cell Reports.

Jo’s lab is in the Wallace H. Coulter Department of Biomedical Engineering at Emory and Georgia Tech.

Previously, when they saw inflammation in blood vessels, researchers could not distinguish between intrinsic changes in endothelial cells and immune or other cells infiltrating into the blood vessel lining.

A video made by Harvard scientists who developed the single cell techniques describes the difference like this. Looking at the molecules in cells with standard techniques is like making a fruit smoothie – everything is blended together. But single cell techniques allow them to taste and evaluate each piece of fruit individually.

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Posted on December 15, 2020 by Quinn Eastman in Heart Leave a comment

Deliver, but not to the liver

The potential of a gene-silencing technique called RNA interference has long enticed biotechnology researchers. It’s used routinely in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugs in treating human disease.

RNA is unstable and cumbersome, and just getting it into the body without having it break down is difficult. One that hurdle is met, there is another: the vast majority of the drug is taken up by the liver. Many current RNA-based approaches turn this apparent bug into a strength, because they seek to treat liver diseases. See these articles in The Scientist and in Technology Review for more.

But what if you need to deliver RNA somewhere besides the liver?

Biomedical engineer Hanjoong Jo’s lab at Emory/Georgia Tech, working with Katherine Ferrara’s group at UC Davis, has developed technology to broaden the liver-dominant properties of RNA-based drugs.

Hanjoong Jo, PhD

The results were recently published in ACS Nano. The researchers show they can selectively target an anti-microRNA agent to inflamed blood vessels in mice while avoiding other tissues.

“We have solved a major obstacle of using anti-miRNA as a therapeutic by being able to do a targeted delivery to only inflamed endothelial cells while all other tissues examined, including liver, lung, kidney, blood cells, spleen, etc showed no detectable side-effects,” Jo says. Read more

Posted on September 1, 2015 by Quinn Eastman in Heart Leave a comment

The other “cho-” cardiovascular disease biomarker

Quick, what biomarker whose name starts with “cho-” is connected with cardiovascular disease? Very understandable if your first thought is “cholesterol.” Today I’d like to shift focus to a molecule with a similar name, but a very different structure: choline.

Choline, a common dietary lipid component and an essential nutrient, came to prominence in cardiology research in 2011 when researchers at the Cleveland Clinic found that choline and its relatives can contribute to cardiovascular disease in a way that depends upon intestinal bacteria. In the body, choline is part of two phospholipids that are abundant in cell membranes, and is also a precursor for the neurotransmitter acetylcholine. Some bacteria can turn choline (and also carnitine) into trimethylamine N-oxide (TMAO), high levels of which predict cardiovascular disease in humans. TMAO in turn seems to alter how inflammatory cells take up cholesterol and lipids.

Researchers at Emory arrived at choline metabolites and their connection to atherosclerosis by another route. Hanjoong Jo and his colleagues have been productively probing the mechanisms of atherosclerosis with an animal model. Very briefly: inducing disturbed blood flow in mice, in combination with a high fat diet, can result in atherosclerotic plaque formation within a few weeks. Jo’s team has used this model to examine changes in gene activation, microRNAs, DNA methylation, and now, metabolic markers.

Talking about this study at Emory’s Clinical Cardiovascular seminar on Friday, metabolomics specialist Dean Jones said he was surprised by the results, which were recently published by the American Journal of Physiology (to be precise, their ‘omics journal). The lead author is instructor Young-Mi Go. Read more

Posted on December 9, 2014 by Quinn Eastman in Heart Leave a comment

Epigenetic changes in atherosclerosis

If someone living in America and eating a typical diet and leading a sedentary lifestyle lets a few years go by, we can expect plaques of cholesterol and inflammatory cells to build up in his or her arteries. We’re not talking “Super-size Me” here, we’re just talking average American. But then let’s say that same person decides: “OK, I’m going to shape up. I’m going to eat healthier and exercise more.”

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Let’s leave aside whether low-carb or low-fat is best, and let’s say that person succeeds in sticking to his or her declared goals. How “locked in” are the changes in the blood vessels when someone has healthy or unhealthy blood flow patterns?

Biomedical engineer Hanjoong Jo and his colleagues published a paper in Journal of Clinical Investigation that touches on this issue. They have an animal model where disturbed blood flow triggers the accumulation of atherosclerosis. They show that the gene expression changes in endothelial cells, which line blood vessels, have an epigenetic component. Specifically, the durable DNA modification known as methylation is involved, and blocking DNA methylation with a drug used for treating some forms of cancer can prevent atherosclerosis in their model. This suggests that blood vessels retain an epigenetic imprint reflecting the blood flow patterns they see.

Although treating atherosclerosis with the drug decitabine is not a viable option clinically, Jo’s team was able to find several genes that are silenced by disturbed blood flow and that need DNA methylation to stay shut off. A handful of those genes have a common mechanism of regulation and may be good therapeutic targets for drug discovery.

Posted on June 24, 2014 by Quinn Eastman in Heart Leave a comment

Blood vessels aren’t straight tubes

For years, scientists like Hanjoong Jo have been telling us that blood vessels are like rivers and streams. Fluid dynamics are important; the patterns of curvature and current influence where sediment — or atherosclerosis — builds up.

One of the biggest possible perturbations of fluid dynamics in a blood vessel would be to stick a metal tube into it. Of course, cardiologists do this all the time. During percutaneous coronary intervention (PCI), doctors place a stent, basically a metal tube, inside a blood vessel to relieve an obstruction and restore blood flow to the heart muscle.

Habib Samady, Emory Healthcare’s director of interventional cardiology, is leading a clinical trial looking at the effects of stent introduction on blood vessels that are not straight, but curved or angulated. To be eligible for the study, the patient’s blocked vessel has to bend more than 30 degrees. The study will look at patients who have undergone PCI for a heart attack and follow them over the course of a year. Less “disturbed flow” should mean better heart healing for the patient down the road. The study uses OCT (optical coherence tomography) and IVUS (intravascular ultrasound) to monitor the blood vessel and see how healing is affected by fluid dynamics after stent placement. Read more

Posted on April 30, 2014 by Quinn Eastman in Heart Leave a comment