Biochemistry's Second Annual Award Symposium

The Department of Biochemistry held its second annual graduate student award symposium on Friday, April 6th.

The symposium featured two speakers who received awards: Dr. Harris, the recipient of the 2017 Biochemistry Trust of Urbana Award for Excellence in Graduate Studies, and William Arnold, who received the 2017 Colin A. Wraight Memorial Award in Biochemsitry for an Outstanding Paper.

Dr. Daniel Harris, Jr. (Kranz lab) shared the work he did on engineering and characterizing human T cell receptors for cancer immunotherapies. His work consisted of using deep sequencing techniques for engineering high-affinity T cell receptors against cancer antigens. The engineered high affinity receptors were then transduced into T cells and tested for activity against cancer antigens.

William Arnold (Das lab) shared his work studying the biochemical mechanisms by which drugs can modify the biosynthesis of cardioprotective compounds through CYP2J2. William’s recent work found that doxorubicin inhibits the biosynthesis of cardioprotective compounds through CYP2J2, and a metabolite of doxorubicin modulates the site of metabolism. They also found that cannabinoids are substrates of CYP2J2 and essentially shut down endocannabinoid metabolism through CYP2J2.

William Arnold's award-winning paper can be viewed here.

The symposium honored several other awards, external fellowships, and recent graduates.

Dr. Kiruthika Selvadurai (Huang lab) received the Anne A. Johnson Work Award for Excellence in Biochemistry.

Julian Reed (Lu lab) received the 2017 School of MCB Outstanding Teaching Assistant.

Xingchen Dong (Chen lab), Matthew Starr (Fratti lab), and Xinyu Kong (Jin Lab) received the 2017 Robert L. Switzer Award for Excellence in Teaching.

Paola Estrada (Nair lab) received the Herbert L Carter Graduate Fellowship.

Andrea Hernandez Garcia received the First-Year Westcott Bioscience Fellow in Biochemistry.

John Khamo received the Westcott Bioscience Fellowship.

Department travel grant awards went to William Arnold, Sushant Bangru, Lu Chen, Paola Estrada, Quan Lam, Mara Liveszey, Gregory Miner, Payel Mondal, Melanie Muller, Amy Carruthers, Xingchen Dong, Jennifer Hou, Iti Kapoor Donald Sheppard, and Liqun Yu.

External fellowships included Joseph Seimetz (Kalsotra lab), American Heart Association; Maxwell Baymiller (Martinis lab), Page Daniels (van der Donk lab), and Imran Rahman (van der Donk lab), Chemistry-Biology Interface Training Grant; Melanie Muller (Tajkhorshid lab), National Institutes of Health; Josephine Watson (Das lab), National Institutes of Health Diversity Supplement; Waqar Arif (Kalsotra lab) and Daniel Harris, Jr. (Kranz lab), National Research Service Award; Mara Livezey (Shapiro lab), National Science Foundation.

Doctor of Philosophy Degrees were conferred for May and December 2017 graduation dates to Dr. Alexander Cioffi (Burke lab), Dr. Shannon Walsh (Silverman lab), Dr. Gus Lawrence (Fratti lab), Dr. Zehua Bao (Zhao lab), Dr. Amruta Bhate (Kalsotra lab) Dr. Ruchia Duggal (Sligar lab), Dr. Seung J. Oh (Blanke lab), and Dr. Julian Reed (Lu lab).

The Department of Biochemistry is grateful for the unwavering support of our alumni and friends that allows us to continue in discovery and public service through teaching, research, and community engagement.

Photos of the symposium can be viewed here.

Posted April 26, 2018
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MCB graduate students serve as role models for middle school girls in Science Social Café

The graduate students are all also members of the MCBees GSA (Graduate Student Association). Passionate about their fields and about research, these women are also passionate about sharing their love of science with students younger than they; in fact, most have been actively participating in many outreach activities, including those organized by the MCBees’. So they all made time in their busy schedules for this particular outreach; however, their primary motivations varied.

Most acknowledged that they came to the Café to serve as role models for the girls. For example, MCB PhD student Andie Liu says that when she was little, her aunt, who is a scientist, was her role model. So her goal in participating in the Café was to possibly be a role model for some of these girls.

“I came today because when I was young, I was hoping that I’d have the chance to interact with a more senior female scientist. I hope this is a good chance to tell the girls here my story.”

Liu studies small molecules produced by bacteria to fight each other, which she indicates are often times antibiotics, and sometimes antifungal. “It’s a nice reservoir for people to find new drugs,” she reports.

Jessica Kelliher, another Ph.D student in MCB, states that she came to the event in order to share about her journey:
“About how I’ve been interested in science and following my passion for science since grade school.”

Plus, she admits that she hoped to “inspire young girls do the same on this international women’s day.”

Kelliher, who studies how Staphylococcus Aureus survives in the human body, more specifically studies how staph competes with the human host for nutrients like iron and zinc.

Along with being role models for the girls, the ladies also came to share with the middle schoolers the idea that there are lots of different, exciting career possibilities in science.

For example, Katie Frye was another MCB PhD student who, growing up, had no idea that she could choose a career in science.

She confesses, “I liked science all along, but I didn’t think it was a career. I didn’t know that graduate school even existed.”

So Frye hoped to “help other little ‘me’s’ that don’t know that science is an option and that there’s actually things you can do. Not just, “Oh, I like science; I’m going to do it in school,’ No, you can actually pursue it for your life.”

Like Kelliher, Frye also studies Staph aureus in Thomas Kehl-Fie’s lab.

Also underscoring the idea that there are lots of great career possibilities in science was PhD student Kristen Farley, also hoped to convey to the girls that if they like science, it would make a great career.

“I came for a lot of the same reasons that Katie came, says Farley. “When I was young, I was interested in science but I didn’t know that you could actually make it your career. I’d like to share that with these girls and give them a role model also.”

Farley’s research involves the study of a microbe that’s not a bacterium, but an Archean, a member of the third domain of life that was actually discovered here on campus by Carl Woese fairly recently. She adds that the microbe is completely anaerobic, which means it’s killed by oxygen and produces methane as a bi-product of its metabolism. She specifically studies microbes that live in the human gut, trying to develop genetic tools to study those organisms.

Like Farley, Pritha Rao also hoped to influence some of the girls toward careers in research. And although she agrees it can make a great career, her main motivation was to recruit some additional help in the field solving some of the problems that need to be addressed. “I came today not only to be an inspiration to them, that there’s a career in science that you can do. There are a lot of unexplored questions out there that we still don’t know the answers to.”

While Rao wanted to be an inspiration to them, she also hoped that they might inspire her as well. “Because these are young girls,” she explains, “they haven’t explored anything, but they are full of energy to explore what is all there. Sometimes as we get older, I think we lose enthusiasm for everyday life. When we get into contact with the young girls, it brings back the enthusiasm. What we are doing is worthwhile, and it’s worth it to spread the message and encourage them.”

Rao, whose research is about how DNA is managed inside the cell, reports that if a cell’s DNA is not duplicated or repaired properly, there are little consequences. “So we are studying how these little consequences can be manipulated in terms of designing new drugs for curing cancer.

Like many of the other ladies, MCB PhD student Mara Livezey participated in the Café for many of the same reasons that these women already stated; she wanted to be a role model and encourage each youngster that a career in science is possible. But she had an even loftier hope—that maybe some of them might end up increasing the pool of female science faculty in higher education.

“There really aren’t that many female faculty,” she acknowledges, “…maybe because they never had women as scientific role models. I think something that’s really good is to expose young girls to, ‘Yes, you can be a scientist.’"

So Livezey also hoped to sow the seed that another possible career they might aspire to is to become a faculty member. “This is something that women can do as well. So hopefully, over time, the percentage of faculty scientists who are women increases to become more equitable.”

Livezey believes that this shortage might be due to a lack of female role models. “I think some of the past, it wasn’t because there was some bias against women in science. It’s good just to have that strong female role model.”

Livezey, who researches breast cancer, indicates that in her lab, they do two different but related things. One is to study the pathway that protects cancer cells and helps them grow. “We want to understand how that works, how it helps them grow, and how it supports things that we already know about breast cancer.”

Her lab is also seeking to develop a drug that actually uses this same pathway, hijacking it and turning it way up to toxic levels in order to kill the cells that way. “My project is studying the drug and seeing how exactly it kills the cells,” she reports, “trying to understand this better and why it works so well.”

Story and photographs by Elizabeth Innes, I-STEM Education Initiative

Posted April 03, 2018
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Professional development workshop aimed at empowering women for successful careers

Dr. Brenda Wilson, professor in the Department of Microbiology and associate director in the School of MCB, provided strategies with a few personal anecdotal examples for navigating and thriving in male-dominated fields.

Tina Knox, coordinator of Undergraduate Instruction and Advising in the School of MCB, joined in a panel discussion of personal accounts of decisions leading to different career paths.

Alejandra Stenger, merit director in the School of MCB, joined a panel discussion about strategies for addressing discrimination and harassment in the workplace, and what options are available.

The event included several other excellent speakers; a full list of presenters can be found here Don't miss next year's event. Follow the Women's Resource Center on Twitter: @IllinoisWRC

Posted March 15, 2018
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Engineering T cells to attack cancer

Findings published in Nature Biotechnology, the Journal of Biological Chemistry, and the Journal of Immunology describe strategies to engineer improved receptors against cancer antigens, and to enhance the properties of the T cells that express these receptors. Over the past three decades, immunologists have developed a type of cancer treatment called adoptive T cell therapy. The approach alters a patient’s own T cells (a type of white blood cell which can be collected from the blood of each patient) by inserting a protein-based receptor that binds to an antigen on the surface of the cancer cells. Once binding occurs, the T cell kills the cancer cell and then serially moves on to the next cancer cell, one by one destroying its cancerous ‘enemies’.

In order to engineer these cancer-seeking T cells, the receptors must be designed to bind optimally to the cancer cell, but not to normal cells in the body. In addition, many other important questions about the receptor:cancer antigen interaction remain. For example, how many cancer antigens are required? How tightly should the receptors bind? Can these receptors be engineered to improve their activity?

Each of these papers addresses some aspect of these questions. In the Nature Biotechnology work, conducted with colleagues Tom Schmitt and Phil Greenberg at the University of Washington, a diverse collection of receptors (called T cell receptors, TCRs) was expressed in progenitor T cells. From these, it was possible to do rapid in vitro selection of those T cells with TCRs that bound well to the cancer cell antigens while at the same time avoiding those T cells that would be reactive with normal cells. This ‘natural selection’ of TCRs could provide advantages for identifying TCRs that are safe and effective for use in patients.

In the work described in the Journal of Biological Chemistry, Preeti Sharma, a postdoc in the lab, discovered that a T cell receptor against a cancer antigen from melanoma could be engineered to improve binding dramatically by taking an approach sometimes called ‘needle in the haystack’ selection. This involved generating a collection of over one million mutant TCRs, mutated at key locations in the structure, and then selecting the few that bind better to the cancer antigen. Unexpectedly, some mutations that bound almost 100-times better were located away from the antigen-binding site.

Finally, in the study published in the Journal of Immunology, Dan Harris, an MD/PhD student, and Marlies Hager, a postdoc in the lab, examined a different question but one of direct importance to the use of adoptive T cell therapies. In addition to T cell receptors, there are many clinical studies involving another class of receptors, called chimeric antigen receptors (CARs). In fact, there are two recent FDA-approved CAR T cell therapies, one against acute lymphoblastic leukemia and one against B-cell lymphoma (KymriahTM from Novartis, and Yescarta™ from Gilead/Kite, respectively). Harris, Hager, and colleagues decided to compare various properties of TCR- and CAR-mediated T cells to understand more about their mechanisms of action, and under what conditions one might be superior to the other. Their salient finding was that TCR T cells were 100-fold more sensitive than CAR T cells, indicating that TCRs should be used when cancer antigens are at low levels.

Collectively, these studies help build on the excitement and potential of immunotherapies. In this case, engineering a patient’s own T cells with the most effective receptors to treat their tumors.

The work was supported by grants from the National Cancer Institute of the National Institutes of Health.

Read the Nature Biotechnology paper here.
Read the Journal of Biological Chemistry paper here.
Read the Journal of Immunology paper here.     
Posted February 11, 2018
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Researchers identify new physiological regulators of the one carbon cycle metabolism. The findings were published in Nature Communications.

The one carbon (1C) cycle plays a critical role in cellular metabolism by providing one carbon groups in the biosynthesis of cellular molecules which support many critical cellular functions, including biosynthesis of lipids, nucleic acids, and proteins, and epigenetic maintenance. These 1C metabolite levels must be tightly regulated, because abnormal levels have been implicated in many human diseases, including cancer, neuro disease, and metabolic disorders. In particular for this study, phosphatidylcholine (PC), produced from phosphatidylethanolamine by methyl transfer from S-adenosylmethionine (SAM) is a major component of the cell membrane and also a key determinant of hepatic lipid levels. Either too much or too little PC leads to fatty liver. Despite its importance, how the PC and SAM levels in the 1C cycle is regulated and what physiological regulators control one carbon metabolism are largely unknown.

In this study, Prof. Kemper and colleagues show unexpected findings that aromatic hydrocarbon receptor (AHR), also known as dioxin receptor, and an orphan nuclear receptor, Small Heterodimer Partner (SHP), are in vivo transcriptional regulators of the 1C cycle. Early after feeding, insulin/protein kinase B signaling mediates translocation of AHR into the nucleus where AHR induces the expression of 1C cycle genes, resulting in the synthesis of PC and SAM. A mechanism is needed to turn off this induction late after feeding when it is no longer needed. Interestingly, in the late-fed state, a hormone, Fibroblast Growth Receptor-15 (FGF15), activates SHP to block the AHR induction, thereby providing the needed mechanism. Further, this AHR-SHP axis regulating hepatic PC and SAM levels is a critical determinant of hepatic lipid levels and is defective in fatty livers of obese mice and also in non-alcoholic fatty liver disease (NAFLD) patients. The AHR-SHP regulatory axis may provide new targets for treatment of NAFLD and other 1C cycle-related diseases, including cancer.

The study was supported by grants from the National Institutes of Health, and a Basic Science Award from the American Diabetes Association to Professor Kemper. The American Heart Association supported Dr. Young Kim with a Scientist Development Award and Dr. Sangwon Byun with a Post-Doctoral Fellowship.

Read the full article here.     
Posted February 09, 2018
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Structural and computational analyses provide the first view of an activated AMPA receptor. Findings published by the Tajkhorshid and Gouaux labs in Cell.

AMPA receptors are transmembrane ion channels that open in the presence of the neurotransmitter glutamate. This can trigger an action potential, and glutamate receptors therefore play critical roles in how neurons communicate. At a synapse between two neurons, AMPA receptors assemble with regulatory proteins, which can change how fast the receptor opens and closes. The most common of these regulatory proteins are TARPs, which act as molecular buoys that surround the receptor in the membrane, and prevent the glutamate-sensing regions from rearranging during receptor desensitization. Structures of TARP-bound AMPA receptors, together with drugs that fully or partially activate the receptor, were solved by cryo-electron microscopy in the lab or Eric Gouaux (OHSU and HHMI). However, these structures were not of sufficient resolution to ‘see’ all the atoms of the receptor, nor could water and ions moving through the channel pore be visualized. Using molecular dynamics simulations, the Tajkhorshid lab computationally modeled the complete structure of the active AMPA receptor with hydrated ions moving through an open pore. Together these findings, published in Cell, show how AMPA receptor regulatory proteins enhance the potency of agonists and alter receptor pore properties, and show how neurotransmitter induces structural rearrangements to open a pore for ions to flow through.

Read the full article here.     
Posted January 26, 2018
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Brooke Lab: Certain Flu Virus Mutations May Compensate for Fitness Costs of Other Mutations

Seasonal flu viruses continually undergo mutations that help them evade the human immune system, but some of these mutations can reduce a virus’s potency. According to new research published in PLOS Pathogens, certain mutations in the genome of influenza A may help counteract the weakening effects of other mutations.

Influenza A causes tens of thousands of deaths in the U.S. every year, despite vaccination efforts. It persists, in large part, due to continual changes in the sequence of amino acid “building blocks” that make up the viral protein hemagglutinin, enabling it to avoid recognition and removal by immune system antibodies. Many of these mutations can reduce a virus’s fitness—its ability to make more copies of itself—raising the question of how viruses compensate to recover their mojo.

Dr. Christopher Brooke, assistant professor of microbiology at Illinois, along with Ivan Kosik of the National Institute of Allergy and Infectious Diseases, Maryland, and colleagues investigated hemagglutinin mutations to better understand the mechanisms by which influenza A viruses maintain fitness despite continual mutation. They focused on influenza A variants with mutations that enabled them to escape antibodies from mice, guinea pigs, or chickens.

To identify the accumulated mutations that restored viral fitness, the researchers sequenced the viral RNA using a supersensitive method called PrimerID sequencing, which enables tracking of all individual viral genomes so that any relevant mutations can be spotted. They found several mutations of particular interest that add a new sugar molecule to the hemagglutinin, thus creating a novel “N-linked glycan” site.

How does this help the virus to replicate? It turns out, that the new sugar allows the virus to regain “Goldilocks” binding to the host cell: not too weak, but not too tight either. In escaping the immune system, the new mutations can inadvertently disrupt this golden binding point, which can be remedied by adding a sugar molecules in the just the part of the hemagglutinin.

These findings improve understanding of the mechanisms that make flu outbreaks so difficult to prevent, and inform efforts to design more effective flu vaccines that are less easily thwarted by continual mutation. The results also demonstrate the value of PrimerID sequencing to provide a high-resolution view of all the mutations present in a given viral population—something that conventional deep sequencing approaches cannot do as accurately or efficiently. This level of understanding is necessary to keep up with the flu, which despite is miniscule size, has managed to outsmart humans trying to foil the havoc it wreak each flu season.

Read the full article here.     
Posted January 18, 2018
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Dr. Brenda Wilson honored with the Dr. Larine Y. Cowen Leadership in Diversity Award

Watch this video to learn more about Dr. Wilson’s leadership in diversity.

The Celebration of Diversity program is an annual event that brings together campus and community leaders to affirm their collective support for an inclusive society and community. This event celebrates the achievements of faculty, academic professionals and civil service employees who make significant contributions in creating and sustaining an inclusive living, learning, and working community at Illinois.

In honor of the past Office of Diversity, Equity, and Access director, Dr. Larine Y. Cowan, the Office of Diversity, Equity, and Access (ODEA) created awards consistent with Dr. Cowan’s values for human rights advocacy, social justice, and diversity. The Larine Y. Cowan Make a Difference Awards recognize, and honor nominees who demonstrate exceptional dedication to and success in promoting diversity and inclusion through teaching, research, hiring practices, courses, programs, and events.

Award categories are as follows;
1. Advocacy for LGBTQ Affairs, honoring students, staff, or faculty who have demonstrated their commitment to supporting and promoting lesbian, gay, bisexual, transgender, and Queer (LGBTQ) affairs at Illinois.
2. Excellence in Access and Accommodations, honoring individuals or campus units for their efforts to expand and improve the utilization of programs and structures by persons with disabilities.
3. Leadership in Diversity, honoring nominees who demonstrate exceptional dedication to and success in promoting diversity and inclusion via research, hiring practices, courses, programs, and events.
4. Teaching and Mentoring in Diversity, honoring faculty, instructors, or lecturers who have consistently contributed to the promotion of understanding critical issues related to diversity and equity in teaching and/or the mentoring of diverse students.

Posted November 15, 2017
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Shape-shifting agent targets harmful bacteria in the stomach

The antimicrobial agent morphs into a bacterial hole-puncher in the stomach’s acidic environment and reverts to an amorphous, inactive structure when it reaches the higher pH environment of the small intestine.

Researchers developed a shape-shifting antibiotic agent that kills infectious H. pylori bacteria in the stomach, but does not kill helpful bacteria in the intestine. Illinois professor Jianjun Cheng led the research team.

Researchers at the University of Illinois and collaborators in China and at Vanderbilt University published their findings in the Proceedings of the National Academy of Sciences. The study leaders were Illinois professors Jianjun Cheng, a Hans Thurnauer Professor of Materials Science and Engineering, and Lin-Feng Chen, a professor of biochemistry.

H. pylori infects the lining of the stomach and is a leading cause of stomach ulcers, gastritis and stomach cancer.

“Fifty percent of the world population will have H. pylori infections in their lifetime,” Cheng said. “It’s a huge market that needs improved solutions, especially in developing countries. Our conformation-switchable polypeptide is the only therapy reported so far that can kill this bacteria at a specific pH range.”

The standard treatment for H. pylori infections requires a cocktail of several antibiotics and an agent to reduce acidity in the stomach so that the antibiotics can work. This has the unfortunate side effect of killing off 65 to 80 percent of other bacteria in the digestive tract, Cheng said – bacteria crucial to maintaining digestive health, nutrient absorption and the immune system.

Cheng’s group previously developed short protein chains that twist into a helical spiral, giving them a stiff, rodlike structure that can punch holes through bacterial membranes – a method of killing to which bacteria have little ability to develop resistance. With a few simple alterations to the side chains that branch out from the polymer backbone, the researchers were able to create a shape-shifting version of the hole-punching agent.

When in the pH range in most body tissues, the proteins are shapeless and limp, unable to get through cell membranes. But at acidic pH the stomach, they curl up into the spiral rod structures, allowing targeted killing of H. pylori.

“This is a very simple solution to this disease,” Cheng said. “These materials become therapeutically effective in the stomach, but once they move to the small intestine – where you have a lot of good bacteria – the pH is neutral or slightly basic and the materials quickly lose their rigid structures. Then they are excreted from the body.”

The researchers tested the drug on mice with H. pylori infections from several different cell lines, and found that the drug was effective against the H. pylori while maintaining populations of healthy gut bacteria. Since the mouse stomach has a slightly higher pH than the human stomach, the researchers believe it will be even more effective in the greater acidity of the human stomach, Chen said.

The researchers are performing tests in large animal models as the next step toward human studies. They have obtained a patent and are working toward commercializing the agent as well.

“Traditional treatment involves complicated drug designs and combinations. This drug is very easy to manufacture and scale up. It’s just a polymer – a polypeptide chain with amino acid building blocks – and it’s biodegradable,” Cheng said.

The National Institutes of Health and the National Science Foundation supported this work.

Story by Liz Ahlberg Touchstone, Biomedical Sciences Editor, News Bureau

Read the full article here.     
Posted November 13, 2017
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Study reveals how bacteria steal nutrients from the host

The study looked at how the bacterium Staphylococcus aureus, which can infect virtually all of the tissues in the human body, competes with the immune system for the essential nutrient zinc.

“Transition metals such as zinc are essential for all forms of life,” said Dr. Kehl-Fie, assistant professor of microbiology. “We get these metals from food, while invading bacteria must get them from us.”

In order to combat an infection, the body’s immune system hoards zinc and other critical nutrients, in an effort to weaken the bacteria. “The host and bacteria are, in effect, engaged in a tug of war for zinc,” said Kehl-Fie. “Our immune system tries to remove zinc from sites of infection and the bacteria, while the bacteria use transporters to pull the metal away from the host.”

Kehl-Fie and colleagues discovered a new system that enables S. aureus to acquire zinc from the human body. The discovery explains how S. aureus is able to grow well even in environments that are very zinc-limited.

“The system we identified represents a new class of zinc transporters. Differing from other zinc transporters, it uses a secreted metal-binding molecule called a metallophore. While metallophores are known to enable bacteria to obtain iron during infection, this is the first example of a bacteria using this strategy to obtain zinc from the host,” said Kehl-Fie.

Dr. Kehl-Fie's lab in collaboration with a team at the Woese Institute for Genomic Biology to discovered that analogous transporters are present in other pathogens as well.

The metallophore molecule can import zinc into the bacteria even when the amount of zinc in the environment is extremely low. This means that, even with the immune system acting in full-force against these bacteria, they can still obtain this essential nutrient in the human body.

“This discovery not only means we know more about how these bacteria infect the human body, but could open up new ways to help fight infection of this type,” said Kehl-Fie.

“The continued emergence and spread of antibiotic resistance highlights the need for new therapeutics to treat bacterial infections,” he said.

Graduate student Kyle Grim was the lead author of the paper. The Kehl–Fie lab is supported by the NIH, March of Dimes, and the Vallee Foundation.

Serina Taluja, MCB communications, contributed to this story.

Read the full article here.     
Posted October 31, 2017
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Cholesterol byproduct hijacks immune cells, lets breast cancer spread

High cholesterol levels have been associated with breast cancer spreading to other sites in the body, but doctors and researchers don’t know the cause for the link. A new study by University of Illinois researchers found that the culprit is a byproduct of cholesterol metabolism that acts on specific immune cells so that they facilitate the cancer’s spread instead of stopping it.

The study, published in the journal Nature Communications, identifies new potential drug targets that could inhibit the creation or actions of the dangerous cholesterol byproduct, a molecule called 27HC.

“Breast cancer impacts roughly 1 in 8 women. We’ve developed fairly good strategies for the initial treatment of the disease, but many women will experience metastatic breast cancer, when the breast cancer has spread to other organs, and at that point we really don’t have effective therapies. We want to find what drives that process and whether we can target that with drugs,” said Erik Nelson, a professor of molecular and integrative physiology who led the study.

Nelson’s group fed mice with breast cancer tumors a diet high in cholesterol. The researchers confirmed that high levels of cholesterol increased tumor growth and metastasis, and that mice treated with cholesterol-lowering drugs called statins had less metastasis. Then they went further, specifically inhibiting the enzyme that makes 27HC during cholesterol metabolism.

“By inhibiting the enzyme that makes 27HC, we found a suppressor effect on breast cancer metastasis. This suggests that a drug treatment targeting this enzyme could be an effective therapeutic,” said Amy Baek, a postdoctoral researcher at Illinois and the first author of the paper.

The researchers also saw unusual activity among specific immune cells – certain types of neutrophils and T-cells – at metastatic sites high in 27HC.

“Normally, your body’s immune system has the capacity to attack cancer,” Nelson said, “but we found that 27HC works on immune cells to fool them into thinking the cancer is fine. It’s hijacking the immune system to help the cancer spread.”

See a video of Nelson describing the study on YouTube.

Because 27HC acts through the immune system, and not on the breast cancer itself, the researchers believe their findings have broad applicability for solid tumors. They performed experiments looking at colon cancer, lung cancer, melanoma and pancreatic cancer, and found that 27HC increased metastasis for all the tumor types, suggesting that a treatment targeting 27HC could be effective across multiple cancer types.

The researchers are working to further understand the pathway by which 27HC affects the immune cells. With clinical partners at Carle Foundation Hospital in Urbana, the team is working to establish whether 27HC has the same pathway in human patients as in mice.

“We hope to develop small-molecule drugs to inhibit 27HC,” Nelson said. “In the meantime, there are good cholesterol-lowering drugs available on the market: statins. Cancer patients at risk for high cholesterol might want to talk to their doctors about it.”

Nelson also is affiliated with the Cancer Center, the division of nutritional sciences and the Carl R. Woese Institute for Genomic Biology at Illinois. The National Institutes of Health and the Susan G. Komen Foundation supported this work.

By Liz Ahlberg Touchstone, Biomedical Sciences Editor, News Bureau

Posted October 12, 2017
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Dr. Susan Martinis, Head of biochemistry, named interim vice chancellor for research

“Professor Martinis has earned a reputation here at Illinois as a collaborative scholar and consultative leader who gets work done. These qualities make her an ideal fit for this role,” said Robert Jones, chancellor of U of I’s Urbana-Champaign campus, in an announcement on Friday.

The outgoing vice chancellor for research, Peter Schiffer, announced his departure in August.

Martinis, who holds the Stephen G. Sligar Professorship in the School of Molecular and Cellular Biology, also serves as interim director for biomedical science and engineering in the Carle Illinois College of Medicine. She is recognized as a groundbreaking researcher, a decorated teacher and one of the most respected academic administrators on the campus, Jones said.

Martinis joined the Department of Biochemistry at Illinois as an associate professor in 2005 and became a full professor in 2009. In addition to her service as head of biochemistry, she also served as an associate dean for LAS. She also served as head of the department of medical biochemistry for the Regional College of Medicine’s operation on the Urbana campus.

Her research into the mechanisms, evolution and biomedical applications of protein synthesis and RNA-protein interactions has been supported by the National Institutes for Health and the National Science Foundation and earned her recognition as a University Scholar.

She also has significant experience in the private sector, working to launch the lifesaving antibiotic Cubicin while at Cubist Pharmaceuticals (acquired by Merck in 2014). Martinis earned her doctoral degree in biochemistry at Illinois and trained at MIT as an American Cancer Society Postdoctoral Fellow.

“I want to thank Peter Schiffer for his outstanding service and leadership as vice chancellor at Illinois,” Jones said. “He leaves us with a research enterprise and infrastructure that is robust, resilient, sustainable and positioned for continued growth and excellence.”

Jones added: “Please join me in congratulating – and thanking – Professor Susan Martinis as she takes on this critical responsibility for us. I am confident that the research enterprise will not only continue to thrive, but also grow under her leadership.”

Posted September 29, 2017
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Dr. Thomas Kehl-Fie Named 2017 Vallee Scholar

The Vallee Scholars Program recognizes outstanding early career scientists at a critical juncture in their careers. It provides $250,000 in discretionary funds for basic biomedical research. Candidates are competitively selected based on their originality, innovation, and quality of the proposal, in addition to their record of accomplishment.

Using an interdisciplinary approach, which combines microbiological and biochemical approaches with advanced elemental analysis, the Kehl-Fie group is working to understand how pathogens maximize their ability to compete with the host for essential nutrients and elucidate the adaptations that enable bacteria to grow even when nutritional immunity prevents them from satiating their appetite.

Due to the continued emergence and spread of antibiotic resistance, more than 10 million people per year are expected to die worldwide from infectious diseases exceeding the number of people who die from cancer by 2050. Elucidating how bacteria overcome the host’s defenses has the potential to identify new opportunities for therapeutic intervention and blunt the growing threat of infection.

Dr. Kehl-Fie is an assistant professor of microbiology in the School of Molecular and Cellular Biology. He is also an affiliate member of the Carl R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign.

The Vallee Foundation was established by Bert L and N Kuggie Vallee as their legacy to the advancement of medical science and medical education. The Foundation stimulates development of interdisciplinary sciences related to human health by promoting interaction between productive scientists worldwide.

Posted September 13, 2017
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Study reveals how thiamine affects the gut microbe, B. thetaiotaomicron

The study identified the diverse strategies employed by Bacteroidetes, a widespread and important group of microbes that also inhabit the human gut, to acquire thiamine. All microbes require thiamine, and Bacteroidetes can make their own, take it in from the environment or both. Experiments by Zachary Costliow, a graduate student in the laboratory of microbiology professor Patrick Degnan, revealed that both thiamine biosynthesis and transport are crucial for the surivial of B. thetaiotaomicron in a competitive environment.

Humans require thiamine as well. “Thiamine, or Vitamin B1, is found in whole grains, meat, and fish, and is essential for metabolizing carbohydrates and maintaining the health of the central nervous system,” Costliow said. “Thiamine deficiencies can lead to serious problems with vision, stability, and memory, among other effects.”

In addition to dietary sources, there is evidence that thiamine availability is modulated by or acquired from the dense and diverse microbial communities present in the gastrointestinal tract. As such, the new study contributes to understanding how microbial mechanisms influence the availability of this essential vitamin, the researchers said.

Degnan, the principal investigator on the research, said that diseases such as diabetes, Alzheimer’s, obesity, and even cancer are associated with radical changes in the composition of the gut’s microbes.

“Thiamine influences how the gut’s microbial community is structured, and that means thiamine may be an excellent target for developing treatments for these diseases,” he said.

The Degnan lab’s research is funded by an investigator award from the Roy J. Carver Charitable Trust to PHD (#15-4501), and School of MCB at the University of Illinois at Urbana-Champaign.

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Posted September 07, 2017
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Glial cell line-derived neurotrophic factor signaling inhibits development of the prostate gland

Eric Bolton
Molecular and Integrative Physiology Assistant Professor Eric Bolton. Immunohistochemistry for KRT5, a basal epithelial antigen, and KRT8, a luminal epithelial antigen, shows that luminal epithelial cells are absent from prostate epithelial (PrE) buds of Ret WT urogenital sinuses co-treated with androgen and GDNF compared to those treated with androgen alone. In contrast, luminal epithelial cells are present at PrE buds in DHT-induced Ret KO urogenital sinuses regardless of GDNF exposure. Adapted from Park and Bolton (Development 2017).

The prostate gland is formed from the embryonic urogenital sinus, where the urethra joins the bladder. The androgen receptor (AR) is required for prostate development, and AR signaling acts in concert with other signaling pathways to orchestrate the proliferation and differentiation of mesenchymal and epithelial cells of the developing prostate. Importantly, the disruption of AR-mediated prostate development predisposes humans and rodents to prostate neoplasia by altering the gland’s phenotype early in life.

The study by Park and Bolton demonstrates that RET-mediated GDNF signaling in the mouse urogenital sinus increases proliferation of mesenchymal cells and suppresses androgen-induced proliferation and differentiation of prostate epithelial cells, thereby inhibiting prostate development. The study also establishes novel reciprocal regulatory crosstalk between AR and GDNF signaling in the cellular and molecular mechanism of androgen-induced prostate development. The researchers propose that the reciprocal regulatory crosstalk may serve to balance GDNF-induced proliferation of mesenchymal cells with androgen-induced proliferation and differentiation of prostate epithelial cells, which are mediated by AR signaling in mesenchymal cells. Thus, if the GDNF signaling pathway is not downregulated early in prostate development, elevated levels of GDNF signaling may lead to disruption of AR-mediated prostate development and increased risk for prostate neoplasia.

The National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health and the Campus Research Board at the University of Illinois funded this research.

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Posted August 25, 2017
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Professor Satish Nair, postdoctoral researcher, Shi-Hui Dong, and colleagues find that slowing dangerous bacteria may be more effective than killing them

Researchers at the University of Illinois have discovered a mechanism that allows bacteria of the same species to communicate when their survival is threatened. The study suggests that it may be possible to slow dangerous infections by manipulating the messages these microbes send to each other, allowing the body to defeat an infection without causing the bacteria to develop resistance to the treatment.

The study, reported in the Proceedings of the National Academy of Sciences, builds on work conducted by other researchers at Illinois, including biochemist John Woodland Hastings, who died in 2014, and John Cronan, a professor and the head of the department of microbiology.

“Bacteria are intelligent little organisms. They can survive almost anywhere and quickly adapt to new conditions,” said U. of I. biochemistry professor Satish Nair, a co-author of the study with postdoctoral researcher Shi-Hui Dong and other colleagues.

When bacteria compete with other microbes for scarce resources, the more successful group will produce a unique molecule – an antibiotic – to kill off the other species. When population growth of one group of bacteria outpaces availability of the nutrients it needs to survive, the group produces another unique molecule that tells it to go into a dormant, but more virulent, state and slow growth until more food is available, Nair said.

“Ever since Alexander Fleming discovered penicillin in 1928, we have been using antibiotic molecules developed by one microorganism to kill another microorganism,” Nair said. “Unfortunately, the bacteria have quickly adapted to resist antibiotics, and in a short time, antibiotics will be ineffective.

“On average, nearly every species of bacteria is resistant to at least one antibiotic. Two years ago, researchers in Europe and Asia discovered a so-called superbug that is resistant to all known antibiotics,” Nair said. “Bacteria can share adaptations very easily, and there are so many bacteria with different adaptations to share, which is why they can develop resistance so quickly.”

“Broad-spectrum antibiotics and the overuse of antibiotics are problematic because antibiotics kill off many types of bacteria, even good ones, and the survivors figure out ways to adapt, sharing their strategies with other bacteria,” Dong said.

“No pharmaceutical company is going to invest in 10 years’ worth of research and development if a new antibiotic has a shelf-life of only two years,” Nair said. “It’s not enough time to recover the costs of production.”

Nair and Dong’s new study targets the language, or group signal, that bacteria use to slow down growth rather than the antibiotic signal to kill. The researchers say understanding how bacteria produce the dormancy-signal molecule paves the way for developing molecules that can disrupt the communication of specific bacteria, with little chance for drug resistance to develop.

“We don’t need to kill bacteria to treat disease and infection; we can just slow them down and make them less potent,” Nair said. “That way, there is little chance for any resistance to develop.”

Nair is an affiliate of the Carl R. Woese Institute for Genomic Biology at Illinois. Research in the Nair lab is funded by the National Institutes of Health.

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Posted August 17, 2017
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Auinash Kalsotra Awarded MDA Grant for Studying Myotonic Dystrophy

Assistant professor of biochemistry, Auinash Kalsotra, has been awarded a nationally competitive research award from Muscular Dystrophy Association (MDA). Created in 1950, the MDA is the country’s largest private funder of research pursuing cures and treatments for over 40 neuromuscular diseases, including muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and Friedreich’s ataxia (FA). The grant to Prof. Kalsotra provides $300,000 over a three-year period to study the molecular basis for cardiac arrhythmias in Myotonic Dystrophy, a multi-systemic disease that affects about 1 in 8000 people with no cure.

“Myotonic dystrophy type I (DM1) is caused by an unusual mutation in which a small DNA segment of the mutated gene is repeated hundreds of times”, said Kalsotra. “The mutated gene, when copied into RNA, becomes toxic and particularly harmful because instead of its normal exit to the cytoplasm, the RNA with repeats gets trapped within the nucleus, which alters the normal function of many genes, not just the gene with the mutation,” he explained.

While the mutation affects multiple tissues, cardiac defects – particularly arrhythmias – are the second leading cause of death amongst DM1 individuals; however, the underlying mechanism(s) responsible remain poorly understood. The Kalsotra laboratory is investigating the disrupted function of a previously unknown RNA binding protein in DM1 cardiac pathogenesis. The team will be using novel CRISPR based mouse models, in vitro cell culture systems, and next-generation sequencing approaches to decipher the exact role of this RNA binding protein in promoting cardiac arrhythmias in DM1.

The mission of the MDA is to build the field of neuromuscular disease research, while simultaneously nurturing clinical care to significantly improve both quality and length of lives for those affected by neuromuscular diseases. MDA annually invests over $40 million on research projects. All grant applications go through a rigorous peer-review process by MDA’s Medical and Scientific Advisory Committees, composed of world-renowned experts in neuromuscular diseases. Each year, about 500 researchers apply to MDA for funding; only the top 10-15% of proposals typically receive support. This puts Prof. Kalsotra in an elite club of neuromuscular disease researchers around the globe who, for more than 60 years, have brought hope to countless individuals.

“The value of MDA research funding cannot be underestimated in making this line of investigation possible in my laboratory. The support of MDA allows us to generate exciting new tools for research and study previously unrecognized pathogenic mechanisms for this debilitating disease, ” said Kalsotra. Prof. Kalsotra holds appointments in the School of Molecular and Cellular Biology and Carl. R. Woese Institute for Genomic Biology at the University of Illinois at Urbana-Champaign.

Posted August 03, 2017
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Study: Omega-3 Fatty Acids Fight Inflammation via Cannabinoids

Chemical compounds called cannabinoids are found in marijuana and also are produced naturally in the body from omega-3 fatty acids. A well-known cannabinoid in marijuana, tetrahydrocannabinol, is responsible for some of its euphoric effects, but it also has anti-inflammatory benefits. A new study in animal tissue reveals the cascade of chemical reactions that convert omega-3 fatty acids into cannabinoids that have anti-inflammatory benefits – but without the psychotropic high.

The findings are published in the Proceedings of the National Academy of Sciences.

Foods such as meat, eggs, fish and nuts contain omega-3 and omega-6 fatty acids, which the body converts into endocannabinoids – cannabinoids that the body produces naturally, said Aditi Das, a University of Illinois professor of comparative biosciences and biochemistry, who led the study. Cannabinoids in marijuana and endocannabinoids produced in the body can support the body’s immune system and therefore are attractive targets for the development of anti-inflammatory therapeutics, she said.

In 1964, the Israeli chemist Raphael Mechoulam was the first to discover and isolate THC from marijuana. To test whether he had found the compound that produces euphoria, he dosed cake slices with 10 milligrams of pure THC and gave them to willing friends at a party. Their reactions, from nonstop laughter, to lethargy, to talkativeness, confirmed that THC was a psychotropic cannabinoid.

It wasn’t until 1992 that researchers discovered endocannabinoids produced naturally in the body. Since then, several other endocannabinoids have been identified, but not all have known functions.

Cannabinoids bind to two types of cannabinoid receptors in the body – one that is found predominantly in the nervous system and one in the immune system, Das said.

“Some cannabinoids, such as THC in marijuana or endocannabinoids can bind to these receptors and elicit anti-inflammatory and anti-pain action,” she said.

“Our team discovered an enzymatic pathway that converts omega-3-derived endocannabinoids into more potent anti-inflammatory molecules that predominantly bind to the receptors found in the immune system,” Das said. “This finding demonstrates how omega-3 fatty acids can produce some of the same medicinal qualities as marijuana, but without a psychotropic effect.”

The study was an interdisciplinary effort led by recent comparative biosciences alumnus Daniel McDougle and supported by current biochemistry graduate student Josephine Watson. The team included U. of I. animal sciences professor Rodney Johnson; U. of I. bioengineering professor Kristopher Kilian; Michael Holinstat, of the University of Michigan; and Lucas Li, the director of the Metabolomics Center at the Roy J. Carver Biotechnology Center at Illinois.

Das also is an affiliate of the Department of Biochemistry and the Beckman Institute for Advanced Science and Technology at Illinois.

The National Institutes of Health and the American Heart Association supported this research.

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Posted July 18, 2017
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