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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apoptosis

Anticancer strategy: expanding what is druggable

Scientists at Winship Cancer Institute, Emory University have identified compounds that stop two elusive anticancer targets from working together. In addition to striking two birds with one stone, this research could expand the envelope of what is considered “druggable.”

fx1-1Many of the proteins and genes that have critical roles in cancer cell growth and survival have been conventionally thought of as undruggable. That’s because they’re inside the cell and aren’t enzymes, for which chemists have well-developed sabotage strategies.

In a twist, the potential anticancer drugs described in Cancer Cell disable an interaction between a notorious cancer-driving protein, MDM2, and a RNA encoding a radiation-resistance factor, XIAP.

The compounds could be effective against several types of cancer, says senior author Muxiang Zhou, MD, professor of pediatrics (hematology/oncology) at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center.

In the paper, the compounds show activity against leukemia and neuroblastoma cells in culture and in mice, but a fraction of many other cancers, such as breast cancers (15 percent) and sarcoma (20 percent), show high levels of MDM2 and should be susceptible to them.

Read more

Posted on September 22, 2016 by Quinn Eastman in Cancer 1 Comment

Transformative awards for Mocarski’s malleable cells, lung fibrosis

The National Institutes of Health has announced a five-year, $1.9 million Transformative Research Award to Emory virologist Edward Mocarski, PhD for his work on how the mechanisms of programmed cell death can be subverted.

Mocarski is Robert W. Woodruff professor of microbiology and immunology at Emory University School of Medicine and Emory Vaccine Center. His research, which originated in probing how cells commit suicide when taken over by viruses, could lead to advances in regenerative medicine and organ transplant.

Barker Mocarski

Thomas Barker, PhD (left) and Edward Mocarski, PhD (right)

The grant, funded through the National Institute of Allergy and Infectious Diseases, is one of nine “high-risk-, high-reward” Transformative Research Awards (13 recipients) announced by the NIH on October 6.

In the same group this year, Thomas Barker in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University received a Transformative Research Award for his research on mechanosensors + pulmonary fibrosis.

The Transformative Research Award program supports “exceptionally innovative, unconventional, paradigm-shifting research projects that are inherently risky and untested.” Emory has achieved only one other TRA since the program was established in 2009: Shuming Nie’s project on imaging to guide cancer surgery. Read more

Posted on October 7, 2015 by Quinn Eastman in Immunology Leave a comment

Cell death drug discovery: come at the king, you best not miss

It may seem like a stretch to compare an enzyme to a notorious criminal, especially one as distinctive as Omar Little, a character from the HBO drama The Wire played by Michael Kenneth Williams.

But stick with me, I’ll explain.

TheWire-OmarLittle2-Portable

Omar is a stick-up man who robs street-level drug dealers. When drug dealer henchmen Stinkum and Weebay ambush him, they are unsuccessful and Stinkum is killed. Omar tells Weebay, who is hiding behind a car: “Come at the king, you best not miss.”

At Emory, Ed Mocarski, Bill Kaiser and colleagues at GlaxoSmithKline have been studying an enzyme called RIP3. RIP3 is the king of a form of programmed cell death called necroptosis. RIP3 is involved in killing cells as a result of several inflammation-, infection- or injury-related triggers, so inhibitors of RIP3 could be useful in modulating inflammation in many diseases.

In a new Molecular Cell paper, Mocarski, Kaiser and their co-authors lay out what happened when they examined the effects of several compounds that inhibit RIP3 in cell culture. These compounds stopped necroptosis, but unexpectedly, they unleashed apoptosis, another form of programmed cell death.  Read more

Posted on November 20, 2014 by Quinn Eastman in Immunology Leave a comment

Two angles on cell death

One can take two very different angles when approaching Bill Kaiser’s and Ed Mocarski’s work on RIP kinases and the mechanisms of cell death. These are: the evolutionary where-does-apoptosis-come-from angle, and the anti-inflammatory drug discovery angle.

A pair of papers published this week, one in PNAS and one in Journal of Immunology, cover both of these angles. (Also, back to back papers in Cell this week, originating from Australia and Tennessee, touch on the same topic.)

First, the evolutionary angle.

Cellular suicide can be a “scorched earth” defense mechanism against viruses. Kaiser and Mocarski have been amassing evidence that some forms of cellular suicide arose as a result of an arms race of competition with viruses. The PNAS paper is part of this line of evidence. It shows that the cell-death circuits controlled by three different genes (RIP1, RIP3 and caspase 8) apparently can be lifted cleanly out of an animal. Mice lacking all three genes not only can be born, but have well-functioning immune systems.

Apoptosis is thought to be a form of cellular suicide important for the development of all multicellular organisms. That’s why, to cell and developmental biologists, it seemed rather shocking that researchers can mutate a group of genes that drive apoptosis and other forms of cellular suicide and have adult animals emerge.

Next, the drug discovery angle.

The J. Immunol paper makes that angle clear enough. Most of the authors on this paper are from GlaxoSmithKline’s “Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area.” Here, they show that a mutation in RIP1 inactivating the kinase enzyme protects mice against severe skin and multiorgan inflammation. They conclude their abstract with: “Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.”

Note: TNF-driven inflammatory diseases include rheumatoid arthritis, inflammatory bowel diseases and psoriasis, representing a multibillion dollar market.

 

Posted on May 13, 2014 by Quinn Eastman in Immunology Leave a comment