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

inflammation

Anti-inflammatory drug prevents neuron loss in Parkinson’s model

A lot of evidence has piled up suggesting that inflammation plays a big role in the progression of Parkinson’s.

Immune system genes are linked to disease risk. People who regularly take NSAIDs such as ibuprofen have lower risk. Microglia, the immune system’s ambassadors to the brain, have been observed in PD patients.

Malu Tansey and her postdoc CJ Barnum make a convincing case for an anti-inflammatory — specifically, anti-TNF– therapy to Parkinson’s. They’ve been working with the Michael J. Fox Foundation for Parkinson’s Research to push this promising approach forward. Please check it out.

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Targeting naked DNA in the heart

Hoechst-Structure-300px

The first thing that comes up in a Google search for “Hoechst” is the family of fluorescent dyes used to stain DNA in cells before microscopy. The Hoechst dyes derive their names from their manufacturer: a company, now part of Sanofi, named after the town where it was founded, which is now part of Frankfurt, Germany. The word itself means “highest [spot].”

Although DNA runs the show in every cell, it’s usually well-hidden inside the nucleus or the mitochondria. Extracellular DNA’s presence is a signal that injury is happening and cells are dying.

Biomedical engineer Mike Davis and collaborator Niren Murthy have been exploiting the properties of a DNA-binding dye called Hoechst 33342, often used to stain DNA in cells before microscopy. The dye can only bind DNA if it can get to the DNA – that is, if membranes are broken. This property makes the dye a good way to target injured tissue, either as an imaging agent or for therapy.

At the recent Pediatric Healthcare Innovation retreat, Davis discussed the potential use of such Hoechst derivatives to diagnose myocarditis (inflammation of the heart muscle) in children.

In addition, in a recent paper published in Scientific Reports, Davis and his colleagues attach the Hoechst dye to the cardioprotective growth factor IGF-1, creating a version of IGF-1 that is targeted to injured heart muscle. The first author of the paper is cardiology fellow Raffay Khan, MD. Screen Shot 2014-04-24 at 1.18.35 PM

IGF-1 has shown a lot of potential for treating heart disease, but it’s not the most cooperative as a drug, because it doesn’t last long in the body and doesn’t stick around in the heart. Linked up to the dye, IGF-1 behaves better. When used to treat mouse hearts after a heart attack, the Hoechst-IGF-1 treated-hearts have better function and less scar tissue (seen here as red).

The authors conclude:

With the broad chemistry surrounding functionalized PEG used to create Hoechst derivatives, it may be possible to target other therapies such as cells, small molecules, and even nanoparticles. We believe that the use of DNA binding agents such as Hoechst can be used to target exposed DNA in other diseases where necrotic cell death plays a critical role and could be used as a platform therapy.

 

 

Posted on by Quinn Eastman in Heart Leave a comment

AHA meeting highlights — an Emory-centric view

Poring over the abundance of information presented at major scientific meetings is like trying to drink from a firehose.  Imposing an Emory-centric filter on this year’s American Heart Association Scientific Sessions meeting in Los Angeles, here are three highlights, with a shoutout to the AHA journal Circulation, which provides a database of meeting abstracts.

Alginate encapsulation, a therapeutic delivery tactic to get stem cells to stay in the heart

Presenter Rebecca Levit, MD, a postdoc in cardiology division chair W. Robert Taylor’s laboratory, was a finalist for an Early Career Investigator Award.

 Stem cell therapies for myocardial repair have shown promise in preclinical trials, but lower than expected retention and viability of transplanted cells. In an effort to improve this, we employed an alginate encapsulation strategy for human mesenchymal stem cells (hMSCs) and attached them to the heart with a biocompatible PEG hydrogel patch in a rat MI model. Encapsulation allows for diffusion of pro-angiogenic cytokines and growth factors made by the hMSCs while maintaining them at the site of implantation…Alginate encapsulated hMSCs attached to the heart with a hydrogel patch resulted in a highly significant improvement in left ventricular function after acute myocardial infarction. The mechanism for this markedly enhanced effect appears to be increased cell survival and retention.

 Note: alginate already has a wide variety of uses, for example in culinary arts and to make dental impressions.

suPAR, a biomarker connected with depression, inflammation and cardiovascular outcomes. Step back, C-reactive protein

Depression, inflammation (Manocha, Vaccarino)

Cardiovascular outcomes (Eapen, Quyyumi)

Coronary microvascular dysfunction (Corban, Samady)

Predicting mental-stress myocardial ischemia via a public speaking test

A study probing myocardial ischemia (a lack of blood flow to the heart) induced by psychological stress, described in this Emory Public Health article. The presentation by Ronnie Ramadan examines physiological responses to a public speaking test as a way of predicting more severe problems.

Posted on by Quinn Eastman in Heart Leave a comment

The healing spice: curcumin

A recent article in Chemical & Engineering News describes the promising properties of curcumin, a compound derived from turmeric, in models of Alzheimer’s disease.

Curcumin is a component of turmeric

In addition to contributing to curry dishes’ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmeric’s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.

Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcumin’s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.

Several research groups at Emory are investigating curcumin-related compounds.
Dermatologist Jack Arbiser has been interested in curcumin’s antiangiogenic (inhibiting blood vessel growth) properties for several years and reports that he is studying how the compound is metabolized. Chemist Dennis Liotta and his colleagues have identified relatives of curcumin that are more soluble, and thus could be more easily taken up by the body. In particular, chemist James Snyder has been a key driver in designing and synthesizing curcumin-related compounds used by several investigators at Emory and elsewhere (see figure):

Psychiatrists Thaddeus Pace and Andrew Miller have been testing whether  curcumin relatives may have useful properties with depression. Specifically, the curcumin-related compounds may have the ability to interfere with the connection (YouTube video) between inflammation and depression.

Winship Cancer Institute researcher Mamoru Shoji has been exploring how to target curcumin compounds to tumor-associated endothelial cells by linking them to a clotting factor. In the Department of Gynecology and Obstetrics, Friedrich Wieser is examining whether curcumin compounds can be helpful with endometriosis.

Posted on by Quinn Eastman in Cancer 3 Comments

COX-2 and epilepsy: it’s complicated

How much is the development of epilepsy like arthritis?

More than you might expect. Inflammation, or the overactivation of the immune system, appears to be involved in both. In addition, for both diseases, inhibiting the enzyme COX-2 initially looked like a promising approach.

Ray Dingledine, PhD

COX-2 (cyclooxygenase 2) is a target of traditional non-steroid anti-inflammatory drugs like aspirin and ibuprofen, as well as more selective drugs such as Celebrex. With arthritis, selectively inhibiting COX-2 relieves pain and inflammation, but turns out to have the side effect of increasing the risk of heart attack and stroke.

In the development of epilepsy, inhibiting COX-2 turns out to be complicated as well. Ray Dingledine, chair of pharmacology at Emory, and colleagues have a new paper showing that COX-2 has both protective and harmful effects in mice after status epilepticus, depending on the timing and what cells the enzyme comes from. Status epilepticus is a period of continuous seizures leading to neurodegeneration, used as a model for the development of epilepsy.

Postdoc Geidy Serrano, now at the Banner Sun Health Research Institute in Arizona, is first author of the paper in Journal of Neuroscience. She and Dingledine were able to dissect COX-2’s effects because they engineered mice to have a deletion of the COX-2 gene, but only in some parts of the brain.
They show that deleting COX-2 in the brain reduces the level of inflammatory molecules produced by neurons, but this is the reverse effect of deleting it all over the body or inhibiting the enzyme with drugs.

Four days after status epilepticus, fewer neurons are damaged (bright green) in the neuronal COX-2 knockout mice.

Dingledine identified two take-home messages from the paper:
First, COX-2 itself is probably not a good target for antiepileptic therapy, and it may be better to go downstream, to prostaglandin receptors like EP2.
Second, the timing of intervention will be important, because the same enzyme has opposing actions a few hours after status epilepticus compared to a couple days later.

More of Dingledine’s thinking about inflammation in the development of epilepsy can be found in a recent review.

Posted on by Quinn Eastman in Neuro Leave a comment

Neuroinflammation: a different way to look at Parkinson’s disease

Emory physiologist Malu Tansey and her colleagues are using recent insights into the role of inflammation in Parkinson’s disease to envision new treatments. One possible form this treatment strategy could take would be surprisingly simple, and comparable to medications that are approved for rheumatoid arthritis.

Malu Tansey, PhD

Understanding the role of inflammation in Parkinson’s requires a shift in focus. Many Parkinson’s researchers understandably emphasize the neurons that make the neurotransmitter dopamine. They’re the cells that are dying or already lost as the disease progresses, leading to tremors, motor difficulties and a variety of other symptoms.

But thinking about the role of inflammation in Parkinson’s means getting familiar with microglia, the immune system’s field reps within the brain. At first, it was thought that the profusion of microglia in the brains of Parkinson’s patients was just a side effect of neurodegeneration. The neurons die, and the microglia come in to try to clean up the debris.

Now it seems like microglia and inflammation might be one of the main events, if not the initiating event.

“Something about the neurons’ metabolic state, whether it’s toxins, oxidative stress, unfolded proteins, or a combination, makes them more sensitive. But inflammation, sustained by the presence of microglia, is what sends them over the edge,” Tansey says.

She says that several recent studies have led to renewed attention to this area:

  1. In vivo PET imaging using a probe for microglia has allowed scientists to see inflammation starting early in the progression of Parkinson’s (see figure below)
  2. Epidemiology studies show that taking ibuprofen regularly is linked to lower incidence of Parkinson’s
  3. Experiments with animal models of genetic susceptibility demonstrate that inflammatory agents like endotoxin can accelerate neurodegeneration
  4. Genomics screens have identified HLA-DR, an immune system gene, as a susceptibility marker for Parkinson’s (Emory’s Stewart Factor was a co-author on this paper)

Popping a few ibuprofen pills everyday for prevention and possibly damaging the stomach along the way is probably not going to work well, Tansey says. It should be possible to identify a more selective way to inhibit microglia, which may be able to inhibit disease progression after it has started.

Activated microglia in the midbrain and striatum of a Parkinson's patient

Targeting TNF (tumor necrosis factor), an important inflammatory signaling molecule, may be one way to go. Anti-TNF agents are already used to treat rheumatoid arthritis and inflammatory bowel disease. This January, Tansey and her co-workers published a paper showing that a gene therapy approach using decoy TNF can reduce neuronal loss in a rat model of Parkinson’s. More recently, her lab has also shown that targeting the gene RGS10 is another way to inhibit microglia and reduce neurodegeneration in the same models.

It is important to note that in the rat studies, they do surgery and put the gene therapy viral vector straight into the brain. She says it might possible to perform peripheral gene therapy with the microglia, or even anti-TNF medical therapy. In terms of mechanism, decoy (technically, dominant negative) TNF is more selective and may avoid the side effects, such as opportunistic infections, of existing anti-TNF agents.

Posted on by Quinn Eastman in Neuro 1 Comment
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