Marek Michalak, a professor in the University of Alberta's Department of Biochemistry and graduate student Wen-An Wang were part of the team that discovered a direct link between calcium and cholesterol. Credit: Melissa Fabrizio

It's well known that calcium is essential for strong bones and teeth, but new research shows it also plays a key role in moderating another important aspect of healthcholesterol.

Scientists at the University of Alberta and McGill University have discovered a direct link between calcium and cholesterol, a discovery that could pave the way for new ways of treating high blood cholesterol.

The researchers began the work after having their curiosity piqued while studying the role of a calcium-binding protein. They noticed an extreme rise of blood cholesterol concentration in mice when the protein was not present. To follow up on this observation, Marek Michalak with graduate student Wen-An Wang (University of Alberta) and Luis Agellon (McGill University) teamed up with geneticist Joohong Ahnn (Hanyang University, Korea) and discovered that the physiological link between calcium and cholesterol is also preserved in worms.

"There is a mechanism inside the cell that senses when there is not enough cholesterol present and turns on the machinery to make more," said Michalak, a distinguished university professor in the University of Alberta's Department of Biochemistry. "What we found is that a lack of calcium can hide cholesterol from this machinery. If you lose calcium, your synthetic machinery thinks there's no cholesterol and it starts making more even if there is already enough."

High blood cholesterol is a known risk factor for developing heart disease. "Factors that affect blood cholesterol concentration have been studied for a long time," said Agellon, a professor at McGill's School of Human Nutrition. "The general belief was that cholesterol controlled its own synthesis inside of cells, and then we discovered in our labs that calcium can control that function too. Finding this link potentially opens a door to developing new ways of controlling cholesterol metabolism."

The researchers consider their finding a significant step toward developing different approaches to patient care in the future, but there is more work to be done. They are now looking to discover the common factor that allows calcium and cholesterol to communicate with each other in the cell and have received a four-year grant worth $456,000 from the Canadian Institutes of Health Research to continue their work.

Explore further: What you need to know about cholesterol

More information: Wen-An Wang et al, Loss of Calreticulin Uncovers a Critical Role for Calcium in Regulating Cellular Lipid Homeostasis, Scientific Reports (2017). DOI: 10.1038/s41598-017-05734-x

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Scientists uncover a hidden calcium cholesterol connection - Phys.org - Phys.Org

A champion of modern molecular genetics, Model asked questions that changed the way research was conducted. (Photo by Ingbert Grttner, 1988)

Peter Model, an emeritus faculty member who spent the major part of his career at The Rockefeller University, died on June 9 at the age of 84, after a brief period of declining health. Model used genetics, biochemistry, and molecular biology to study the f1 phage, a type of virus that infects Escherichia coli bacteria. His work provided valuable details about the way genes express themselves and control one another.

Peter brought an incisive, inquisitive mind to his research, and was often responsible for the astute question that would push an investigation in the right direction, noted Rockefeller President Richard P. Lifton in a message to university faculty and staff. He enjoyed the camaraderie of his fellow scientists, served as an informal mentor to many junior faculty members who sought his advice, and was an active member of the Rockefeller community until very recently.

Born in Frankfurt in 1933 during the rise of the Nazis, Model and his parents escaped in 1942 to settle in New York. As a young man, he studied economics at Cornell University and Stanford University, served in the United States Army as a first lieutenant, and worked in his fathers investment banking business for a period before earning a Ph.D. in biochemistry from Columbia University.

Peter was a remarkable person who straddled many worlds, says Jeffrey V. Ravetch, Theresa and Eugene M. Lang Professor and head of the Leonard WagnerLaboratory of Molecular Genetics and Immunology at Rockefeller, who was a student in Models lab in the mid-1970s. Perhaps because of his background in economics and finance, he had a different way of looking at things, and he became a great champion of using new approaches in the lab. He was viciously smart, and he always valued substance over style.

When many other people began working with mammalian systems, Peter stuck to his focus on bacterial genetics and remained true to the essence of microbial systems, Ravetch adds. He saw that they would continue to yield valuable discoveries.

Model arrived at Rockefeller in 1967, joining the laboratory of the late Norton Zinder as a postdoctoral fellow. Named assistant professor in 1969 and associate professor in 1975, he was promoted to full professor in 1987. He and Zinder worked closely together in the laboratory, and Model became co-head of the lab in 1987. From 1992 to 1995, he also served as associate dean of curriculum under deans Bruce McEwen and later Zinder.

Bacterial viruses, or phages, are among the simplest of biological entities and contain only a handful of genes. Models work with them opened a number of new lines of research. He championed the use of several modern molecular genetic techniques, and used these methods to examine, among other things, how phage proteins translocate across bacterial membranes. He developed phage display, which became a widely used method for identifying interactions between proteins. Using this and other techniques, he explored key biochemical processes in the lifecycles of phages.

Models strong commitment to the education and training of younger scientists led him to serve as the primary advisor for a number of graduate students and postdocs during his tenure at Rockefeller.

Peter had a way of asking questions that could change the direction of research, says his wife, Rockefeller associate professor Marjorie Russel, with whom he collaborated. He was famous for incorporating his knowledge from diverse areas and putting everything together in ways that no one else had ever thought of before. Often, after talking to Peter, his students and colleagues would go back to their lab benches with completely new ideas about what to do and where to go with their research.

In addition to his wife, Model is survived by his children, Paul and Sascha; his brother, Allen; and four grandchildren, as well as many other relatives and friends.

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Geneticist and Rockefeller emeritus Peter Model dies at 84 - The Rockefeller University Newswire

COLLEGEVILLE >> U.S. Rep. Ryan Costello, R-6th Dist., visited Ursinus College on July 6 to announce a National Science Foundation grant.

The grant was in the amount of $28,531 for the project, Collaborative Research, which is researching using protein function prediction to promote hypothesis-driven thinking in undergraduate biochemistry education.

Costello, a member of the STEM Caucus, had the opportunity to meet with Rebecca Roberts, an associate professor of biology, and biochemistry and molecular biology at Ursinus College, as well as several students to hear about their research projects.

Im pleased to see students in our community will benefit from a grant that will enable first-hand experiences to encourage them to think like a scientist and, in turn, explore opportunities in STEM education. This grant will also help faculty understand how students learn from these techniques, Costello said in a prepared release.

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I am aiming to provide even greater opportunities for Ursinus students to experience authentic research by bringing research into their courses. As part of a collaboration with faculty from across the country, I have helped develop a project that challenges students to discover functions for proteins of known structure but with currently unknown function. This grant from the National Science Foundation will allow us to continue to engage our students in this project and to evaluate the impact of the experience on their growth as scientists, said Roberts.

Costello recently signed a bipartisan letter to the House Appropriations Committee requesting robust, continued funding for the NSF in the upcoming 2018 Fiscal Year, and has introduced and supported several pieces of legislation to support students who choose STEM fields.

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Ursinus College gets biochemistry grant from National Science foundation - The Times Herald

Vermont Business Magazine The Northern New England population will be the beneficiary of a new partnership between academic medical centers and primary care practices in rural communities, which will focus on health problems endemic to the region, including cancer, cardiovascular disease, substance abuse, as well as the unique challenges of effective rural health care delivery. A five-year, $20 million National Institutes of Health (NIH) Clinical and Translational Research (CTR) Network grant will fund a joint program between the University of Vermont (UVM) and Maine Medical Center in Portland, Maine to develop and sustain a clinical and translational research infrastructure improving rural and community health for residents of Vermont, New Hampshire and Maine. The grant, awarded through the federally-funded IDeA program, enhances research efforts in states where NIH funding levels have traditionally been lower and rural and medically-underserved communities are a priority.

The program will be collaboratively led by principal investigators Gary Stein, Ph.D., UVM Cancer Center director and Department of Biochemistry chair, and Clifford Rosen, M.D., senior scientist at Maine Medical Center Research Institute. UVM Larner College of Medicine Senior Associate Dean for Research Gordon Jensen, M.D., Ph.D., and Thomas Gridley, Ph.D., interim director of the Center for Molecular Medicine at Maine Medical Center Research Institute, will serve as the grants program coordinators.

According to Jensen, Vermont, New Hampshire and Maine have a similar geographic distribution of patients. This will allow participating primary care physicians to work in partnership with academic medical centers to carry out the programs research initiatives and to meet the needs and challenges throughout the northern New England region.

As a cancer center director, Stein emphasizes the capabilities of the networks six program components to address the underlying causes of the regions greatest health threats from multiple perspectives using a rich variety of expertise and collaborative resources and to make related diseases preventable and treatable.

This grant will allow us to investigate the most effective ways to address shared health care issues, said Stein. The program will derive great benefit from maximally engaging the breadth of expertise we have at the University in concert with our primary care partners.

UVM faculty will co-lead five of the six program areas with faculty from Maine Medical Center. Jan Carney, M.D., M.P.H., associate dean for public health, will co-lead Rural Health Research and Delivery; Frances Carr, Ph.D., professor of pharmacology, will co-lead Translational Research Technologies; Bernard Cole, Ph.D., professor of mathematics and statistics, will co-lead Clinical Research Design, Epidemiology; Jane Lian, Ph.D., professor of biochemistry, will co-lead the Pilot Projects Program; and Kim Luebbers, M.S.H.S., R.N., assistant dean for clinical research, will co-lead Professional Development, Clinical Research Design, Epidemiology. The Tracking and Evaluation program will be led by faculty from the University of Southern Maine.

This $20 million grant reinforces confidence in the tremendous resource that is provided by the Universitynot just in education, but in promoting and protecting the overall health and well-being of our citizens, said Vermont Health Commissioner Mark Levine, MD.Collaborations with the Department of Health will leverage these capabilities to make a difference for Vermonters wherever they live.

Source: UVM 7.12.2017

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NIH awards $20 million to UVM and Maine Medical to address rural health challenges - Vermont Biz

(From left are) Drs. B.R. Achyut; Thaiz F. Borin, postdoctoral fellow and a corresponding author; and Ali S. Arbab. Credit: Phil Jones

It's a metabolite found in essentially all our cells that, like so many things, cancer overexpresses. Now scientists have shown that when they inhibit 20-HETE, it reduces both the size of a breast cancer tumor and its ability to spread to the lungs.

"The drug is reducing the ability of cancer cells to create a distant microenvironment where they can thrive," said Dr. Ali S. Arbab, leader of the Tumor Angiogenesis Initiative at the Georgia Cancer Center and a professor in the Department of Biochemistry and Molecular Biology at the Medical College of Georgia at Augusta University.

Arbab notes that cancer cells are constantly doing test runs, sending cells out into the bloodstream to see if they will take hold. About 30 percent of patients with breast cancer experience spread, or metastasis, of the disease. The most common sites are the lymph nodes, liver, bones and brain, as well as the lungs.

For the preclinical studies by postdoctoral fellow, Dr. Thaiz F. Borin, published in the journal PLOS ONE, the scientists used the drug HET0016, a 20-HETE inhibitor developed to learn more about the metabolite's many functions.

While not ready to say that the drug has potential use in humans, Arbab says the work points toward a new and logical target for reducing tumor spread. He notes that there are already drugs out there, including some over-the-counter anti-inflammatory drugs, which may also inhibit this overexpressed and now destructive pathway.

20-HETE - 20-Hydroxyeicosatetraenoic acid - is a metabolite of arachidonic acid, a fatty acid we make and constantly use for a wide variety of functions like helping make lipids for our cell membranes. 20-HETE also has a wide range of normal functions, including helping regulate blood pressure and blood flow. It's also a known mediator of inflammation, which under healthy conditions can help us fight infection and protect us from cancer and other invaders.

"There is normal function and there is tumor-associated function," says Dr. B.R. Achyut, cancer biologist, assistant professor in the MCG Department of Biochemistry and Molecular Biology and a study coauthor. "Tumors highjack our system and use that molecule against us."

In fact, Arbab's research team has shown that the high production of 20-HETE that occurs in cancer becomes an unwitting provider of almost everything cancer needs to prepare a place to comfortably spread.

Scientists call it the "seed and soil" hypothesis. To spread, cancer cells must detach from the primary site, in this case breast tissue, get aggressive enough to survive travel, gather supporting tissue and blood vessels where they land, take seed and eventually colonize the distant site, in this case, the lungs.

Arbab and his team have shown 20-HETE appears to help prepare this distant site by activating things like protein kinases that can change the function of proteins, their location and what cells they associate with, as well as growth factors that can make cells grow in size, proliferate and differentiate. It can even help make blood vessels, which a tumor will need once it reaches a certain size. 20-HETE also activates signaling kinases that enable cell division. It encourages inflammation-promoting factors like tumor necrosis factor alpha and several of the interleukins, another class of proteins that help regulate the immune response. In this scenario, they are turning up inflammation, which is a hallmark of cancer and other diseases.

"We are going after that tumor microenvironment," says Arbab.

For their studies, they put human breast cancer cells and mouse mammary tumor cells in the mammary fat pad of mice, waited for the cancer to take hold and begin to spread, then intravenously gave mice HET0016 five days per week for three weeks.

They found HET0016 reduced the migration and invasion of tumor cells: 48 hours after the drug was given, cancer cells were less able to move about in small test tubes. The drug also reduced levels of metalloproteinases in the lungs, enzymes that can destroy existing protein structures, so that, in this case, cancer cells can penetrate the area and new blood vessels can grow. It also reduced levels of other key inhabitants of a tumor microenvironment like growth factors as well as myeloid-derived suppressor cells that can help shield cancer from the immune system. "It gets rid of one of the natural protections tumors use, and tumor growth in the lung goes down," Arbab notes.

He, Achyut and their colleague Dr. Meenu Jain, assistant research scientist, reported earlier this year in the journal Scientific Reports that the drug also reduced tumor growth and prolonged survival in an animal model of the highly lethal, rapidly growing and vascular brain tumor, glioblastoma. That finding and related work got the scientists wondering if the research drug - or something similar - could one day help control the typically deadly spread of cancer.

Now they are looking at exosomes, traveling packages all cells send out as a way to communicate and swap substances. In the case of cancer cells, exosomes appear to be packed with items needed to build the supportive environment for their new distant location in the lungs or elsewhere. Once exosomes establish a niche, they send back a signal to the primary site for cancer cells to join them. The scientists want to further pursue the ability of HET0016 to block these cancer-derived packages.

20-HETE's co-opting by cancer has it emerging as a focal point for cancer treatment, says Arbab who has published more than half of the 20-HETE-related studies on the rapidly emerging topic.

Explore further: Cells that make blood vessels can also make tumors and enable their spread

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Spread of breast cancer reduced by targeting acid metabolite - Medical Xpress