Ott Lab news stories
Ott Lab postdoctoral scholar Ibraheem Ali’s latest paper ‘Crosstalk between RNA Pol II C-Terminal Domain Acetylation and Phosphorylation via RPRD Proteins’ has been accepted for publication by Molecular Cell Journal. This will be Dr. Ali’s fourth first-author paper, and will be published later in the year.
Congrats, Ibs!
Ott Lab MD/PhD student Kristoffer Leon passed his qualifying exam on September 21, making him an official PhD candidate! Congrats, Kris!
Second year BMS student and Ott Lab graduate student Camille Simoneau passed her qualifying exam on July 26, making her an official PhD candidate! Congrats, Camille!
On June 22nd, Philip Ansumana Hull successfully defended his thesis and earned his PhD. His thesis work focused on immune aging, T cell biology, and T cell metabolism. This included identifying a novel evolutionary conserved SIRT1-FoxO1 axis that regulates CD8+ memory T cell metabolism and cytotoxicity. His last day in the Ott Lab was July 31st, and he is now off to work for Bristol-Meyers Squibb.
Congratulations, Ansu, and good luck at your new job!
Ott Lab summer intern Juan Torres presented the research he did with postdoc Nathan Meyers on August 1st. Juan’s presentation was entitled “Using Liver Stem Cells to Develop a 3D Model for Studying Hepatitis C”. Juan will return to UCLA in the fall to complete his undergraduate studies.
Great job, Juan!
Kristoffer Leon presented his talk “Pediatric Brainstem Encephalitis Outbreak Investigation with Metagenomic Next-Generation Sequencing” during the Contemporary Clinical Issues Plenary Session at the 2018 American Academy of Neurology Annual meeting in Los Angeles, CA. The abstract was named a 2018 Abstract of Distinction to recognize top scientific achievement in the field.
Complimentary access to the 2018 plenary sessions can be viewed here.
Philip Ansumana Hull successfully gave an oral presentation on “Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1” at the 2018 Keystone Symposia on Immunological Memory: Innate, Adaptive and Beyond, February 25-March 2, 2018, at the Hyatt Regency Austin, Austin, Texas.
Congratulations, Ansu!
Aging proteins have long been shown to protect against age-related diseases, such as cancer, neurodegeneration, and cardiovascular disease. A study by researchers at the Gladstone Institutes now reveals that one such protein could also be targeted to rejuvenate cells in the immune system.
The protein in question is called SIRT1, more commonly known for being activated by red wine. In the new study, published in the Journal of Experimental Medicine, the scientists found that it is also involved in how cells in the immune system develop with age.
They wanted to find out how this anti-aging protein affects a specific category of immune cells known as cytotoxic T cells. These cells are highly specialized guardians of the immune system and their role is to kill cells infected by a virus, damaged cells, or cancer cells.
“Over the course of a person’s life, with repeated exposure to bacteria and viruses, these T cells mature and eventually lose a protein called CD28,” said Gladstone Senior Investigator Melanie Ott, senior author of the new study. “And as these cells get older, they become more toxic to their environment.”
This aging process is accelerated by persistent viral infections, such as HIV and CMV (human cytomegalovirus). In fact, HIV-infected patients accumulate mature cytotoxic T cells at a much younger age than an uninfected person.
“A higher number of mature cytotoxic T cells in the body has been associated with age-related, autoimmune, and inflammatory diseases,” added Ott, who is also a professor in the Department of Medicine at UC San Francisco. “We wanted to come up with a way to counteract this phenomenon.”
What Happens in Aging Cells
When a young (or naive) T cell is in a resting state, it uses oxygen to “breathe.” Once it is activated to defend the body against a bacteria or virus, it shifts into enhanced glycolysis and uses sugar to get an immediate boost in energy. This is useful to jump into action, but it isn’t sustainable for long-term performance.
“You can think of it like a 60-meter sprint runner who needs a quick boost of energy to finish the race, in comparison to a marathon runner who needs different energy sources to keep going for a long period of time,” said Ott.
As the cells age and lose CD28, they can shift into glycolysis much more quickly if breathing is inhibited. They also lose the anti-aging protein SIRT1. This becomes a problem, as it makes them more toxic to the cells around them.
In the new study, Ott and her team finally explain how this all happens.
“We studied human T cells, isolated from blood donors of all ages, to compare mature cytotoxic T cells with naive ones,” said Philip Ansumana Hull, graduate student in Ott’s lab and one of the first authors of the study.
They found that naive T cells have a high concentration of SIRT1. This stabilizes an entire mechanism that prevents the cells from entering glycolysis to use sugar as an energy source, and limits their toxic effects.
As the cells age, they lose SIRT1, which changes their basic metabolism. They can then rapidly shift into glycolysis and start producing more toxic proteins called cytokines, which could lead to inflammatory diseases.
One Mechanism to Fight Both Aging and Aggressive Tumors
Based on a better understanding of the crucial role played by SIRT1 in the aging of T cells, the researchers identified two potential new drug targets.
First, new drugs could be developed to strengthen SIRT1 to rejuvenate mature cytotoxic T cells or keep them from progressing too quickly into a highly toxic state.
“This could postpone the development of age-related diseases,” said Mark Y. Jeng, the study’s other first author and former graduate student in Ott’s lab. “It could also help people with a weaker immune system fight infections or better respond to immune vaccination, such as seniors or chronically-infected patients.”
Alternatively, drugs could be used to obtain the opposite effect and encourage the T cells to be more toxic. By temporarily making young T cells more aggressive and behave like mature cells, they could, for example, support an aggressive anti-tumor response or other immune therapeutic approaches.
Publication: Jeng MY, Hull PA, Fei M, Kwon H-S, Tsou C-L, Kasler H, et al. Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1. J Exp Med. 2017 Nov 30. em.20161066; DOI: 10.1084/jem.20161066
Ibs Ali was awarded the Robert D. Watkins Graduate Research Fellowship from the American Society for Microbiology. It also means that you will be supported to travel to the ASM Microbe meeting, and provide you with access to career advancement workshops provided by ASM. Congratulations, Ibs!
Congratulations, Melanie for being honored for your work with the Promoting Underrepresented Minorities Advancing in the Sciences (PUMAS) internship program by the California Life Sciences Association (CLSA). PUMAS supports educational activities that enhance diversity in biomedical research. Established in 2014 by Melanie Ott and Kathy Ivey at the Gladstone Institutes, the program encourages students from historically underrepresented backgrounds, who are currently attending a community college, to pursue undergraduate and graduate degrees in science, technology, engineering, or mathematics (STEM).
Each summer, qualified students are matched with a scientific mentor to gain hands-on biomedical research experience in a Gladstone laboratory. To date, 24 interns have gone through the PUMAS program, and three have since returned to Gladstone as research associates.
The PUMAS program is funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. To ensure their work does the greatest good, Gladstone researchers focus on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone has an academic affiliation with the University of California, San Francisco.